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CORK Bibliography: Immune System

93 citations. January 2003 to present

Prepared: March 2008

Al-Ghamdi HS; Anil S. Serum antibody levels in smoker and non-smoker Saudi subjects with chronic periodontitis. Journal of Periodontology 78(6): 1043-1050, 2007. (73 refs.)

Background: Cigarette smoking is a significant risk factor for the initiation and progression of periodontal disease. Studies have shown altered serum and gingival crevicular fluid inflammatory cytokine profiles, immune cell function, and altered proteolytic regulation in smokers. The observations are not consistent, and to date, there is no clear mechanism to explain how smoking may affect periodontal disease. Hence, the present study was undertaken to assess the alterations of serum immunoglobulin levels in smokers with periodontitis and its potential role as a risk indicator of the disease process. Methods: In this study, 30 patients who smoked and 30 patients who did not smoke with chronic periodontitis and 30 healthy subjects were enrolled. Serum immunoglobulin (Ig) G, IgA, and IgM levels were estimated with immunoturbidimetric assay. The IgG subclass (IgG1, IgG2, IgG3, and IgG4) levels were performed using single radial immunodiffusion assay. Results: Levels of serum IgG and IgA were significantly lower in smokers compared to non-smokers and healthy controls (P < 0.001). Although IgM levels were low in smokers, it was not significant. Of the four subclasses of IgG studied, the IgG2 was found to be significantly lower among smokers with periodontitis. Conclusions: Current observations indicate that cigarette smoking may be associated with the suppression of B-cell function and immunoglobulin production. The alteration of antibody levels further explains the potential mechanism by which smoking exacerbates periodontal disease. Further studies at the molecular level may highlight the specific mechanism by which tobacco can interact with cells of the immune system and its impact on periodontal disease process.

Ashcroft RE; Franey C. Further ethical and social issues in using a cocaine vaccine: Response to Hall and Carter. Journal of Medical Ethics 30(4): 341-343, 2004. (19 refs.)

Evaluation of the potential of a cocaine vaccine requires a detailed understanding of the intended and unintended social consequences of its use. Prospective technology assessment is always difficult, but in the case of treatment and prevention of cocaine addiction we need to understand not only the neuroscience and pharmacology of cocaine addiction, but also social attitudes to drug use and addiction, the social context of drug use, and the factors which make drug use a rational strategy for an addict and make treatment seeking or relapse more or less likely. By considering different scenarios related to differing levels of effectiveness of the vaccine, the authors argue that vaccination will be at best a useful adjunct to existing methods of treatment, rather than a substitute for them.

Besson H; Brennan P; Becker N; Nieters A; De Sanjose S; Font R et al. Tobacco smoking, alcohol drinking and non-Hodgkin's lymphoma: A European multicenter case-control study (Epilymph). International Journal of Cancer 119(4): 901-908, 2006. (60 refs.)

To study the role of tobacco smoking and alcohol drinking in the etiology of non-Hodgkin's lymphoma (NHL), we conducted a multicenter case-control study in Spain, France, Germany, Italy, Ireland and Czech Republic between 1998 and 2004, which included 1,742 cases of NHL and 2,465 controls matched on age, sex and recruitment area. Tobacco smoking was not associated with the risk of NHL overall or with risk of specific histological subtypes. Similarly, there was no association between alcohol drinking and the risk of NHL overall or across histological subtypes. However. a protective effect of alcohol drinking was observed among men (OR = 0.76, 95% CI = 0.62-0.93) and in non-Mediterranean countries (OR = 0.73, 95% CI = 0.61-0.86). There was no evidence of interaction between alcohol drinking and tobacco smoking in NHL etiology. The results of this large-scale European study did not support an association between tobacco and NHL and suggested a protective effect of alcohol on development of NHL for men and in non-Mediterranean countries.

Besson H; Renaudier P; Merrill RM; Coiffier B; Sebban C; Fabry J et al. Smoking and non-Hodgkin's lymphoma: A case-control study in the Rhone-Alpes region of France. Cancer Causes and Control 14(4): 381-389, 2003. (39 refs.)

Objective: To study the relation between smoking and non-Hodgkin's lymphoma (NHL), in the Rhone-Alpes region of France. Methods: We conducted a hospital-based case-control study that included 180 cases of NHL and 360 age-, gender-matched hospital controls. Matched univariable and multivariable logistic regression models were used for analysis. Results: For the whole study population as well as for men, smoking does not elevate the risk of NHL. However, the risk of NHL is higher for women who currently smoke compared to women who have never smoked (odds ratio [OR] = 2.40, 95% confidence interval [95% CI] = 1.19-4.84). Among ever smokers, the OR of NHL is 5.04 (95% CI = 1.40-18.12) for women who have smoked for more than 30 years compared with those who have never smoked. Similarly, women who started to smoke before the age of 20 years compared with women who have never smoked are at greater risk of developing NHL (OR = 2.40, 95% CI = 0.99-5.85). In the total population (women and men), smoking may be associated with one histologic subtype, follicular NHL with an adjusted OR for the current smokers compared to subjects having never smoked of 3.20, 95% CI = 0.79-12.97. Conclusions: In spite of the small number of subjects in the subgroups, a relation is observed between smoking and NHL among women, but not men, and in the total population a relation is suggested between smoking and follicular NHL.

Brown LAS; Cook RT; Jerrells TR; Kolls JK; Nagy LE; Szabo G et al. Acute and chronic alcohol abuse modulate immunity. Alcoholism: Clinical and Experimental Research 30(9): 1624-1631, 2006. (43 refs.)

This article represents the proceedings of the Alcohol and Immunology Research Interest Group (AIRIG) meeting, a satellite workshop held at the 37th Annual Meeting of the Society for Leukocyte Biology. The meeting was sponsored by the AIRIG and the National Institute on Alcohol Abuse and Alcoholism. The presentations were as follows: (1) Effects of Ethanol on Immune Response to Hepatitis C Virus by Jack R. Wands, (2) Alcohol and Alveolar Macrophage Dysfunction: The Role of Chronic Oxidant Stress by Lou Ann S. Brown, (3) T Cell Responses to Listeria monocytogenes in Mice on a Chronic Ethanol Exposure Protocol by Robert T. Cook, (4) Mechanisms of Acute and Chronic Alcohol Consumption on Severity of Viral Infections by the Liver and Pancreas by Thomas R. Jerrells, (5) Acute and Chronic Effects on Macrophage Ectodomain Shedding: Implications for Lung Host Defenses by Jay K. Kolls, (6) Increased Susceptibility to Pseudomonas Infection of Burn-Injured Mice Given Alcohol Before Injury by Elizabeth J. Kovacs, (7) Regulation of Tumor Necrosis Factor alpha Expression in Macrophages by Chronic Ethanol by Laura E. Nagy, and (8) Hepatitis C Virus Infection and Alcohol Use by Gyongyi Szabo. Meeting coorganizers were Elizabeth J. Kovacs, Lou Ann S. Brown, Thomas R. Jerrells, and Robert T. Cook.

Brown LAS; Harris FL; Ping XD; Gauthier TW. Chronic ethanol ingestion and the risk of acute lung injury: A role for glutathione availability? Alcohol 33(3): 191-197, 2004. (38 refs.)

Although pulmonary function is not altered, a history of alcohol abuse is an independent outcome variable in the development of acute respiratory distress syndrome. In the absence of cirrhosis, alcohol abuse decreased glutathione, the key antioxidant lining the alveolar space, by 80% and is associated with alveolar barrier leak. Neither the glutathione pool nor barrier leak was corrected by abstinence for 1 week. This aberrant glutathione homeostasis may contribute to enhanced alveolar permeability, thereby increasing susceptibility to the development of acute respiratory distress syndrome. In a rat model, chronic ingestion of ethanol decreased pulmonary glutathione concentration, increased alveolar barrier permeability, and increased the risk of acute lung injury. In alveolar type II cells, chronic ingestion of ethanol altered cellular functions such as decreased surfactant processing, decreased barrier integrity, and increased sensitivity to cytotoxin-induced apoptosis in vitro and in vivo. In alveolar macrophages, chronic ingestion of ethanol decreased phagocytosis of microorganisms and decreased cell viability, events that would increase the risk of pneumonia. A central role for glutathione availability was demonstrated by the normalization of cellular function and viability of type II cells and macrophages as well as decreased sensitivity to endotoxemia-induced acute lung injury when glutathione precursors were added to the ethanol diet. These results support the suggestion that chronic ingestion of ethanol increased the risk of acute lung injury not through ethanol per se but through the chronic oxidative stress that resulted from ethanol-induced glutathione depletion. Because chronic oxidative stress alters cellular functions and viability, the lung becomes more susceptible when a second hit such as sepsis occurs.

Budney AJ; Moore BA; Vandrey R. Health consequences of marijuana use. IN: Brick J, ed. Handbook of the Medical Consequences of Alcohol and Drug Abuse. Binghamton, NY: Haworth Press, 2004. pp. 171-218. (272 refs.)

There is rather limited research on the chronic effects of marijuana use in terms of health. This chapter provides a review of the existing literature, with particular attention to the respiratory system, immune system, cardiovascular system, endocrine, as well as its impact on reproductive function. There is also attention to the psychological and psychiatric effects of marijuana on psychomotor function, attention, memory, academic performance, driving ability, and motivation. It also touches upon the current discussion of medical use of marijuana.

Carlsson S; Midthjell K; Grill V. Smoking is associated with an increased risk of type 2 diabetes but a decreased risk of autoimmune diabetes in adults: An 11-year follow-up of incidence of diabetes in the Nord-Trondelag study. Diabetologia 47(11): 1953-1956, 2004. (9 refs.)

Aims/hypothesis. We compared the association between smoking habits and later occurrence of type 2 diabetes on the one hand and between smoking and diabetes with autoimmunity on the other hand. Methods. We used data from a prospective study of 11-year cumulative incidence of diabetes in the Nord-Trondelag Health Survey. Results. Confirming previous reports, heavy smoking (greater than or equal to20 cigarettes per day) carried an increased relative risk (RR) of type 2 diabetes (n=738, RR=1.64, 95% Cl: 1.12-2.39). In contrast, smoking reduced the risk of latent autoimmune diabetes in adults (LADA) and of traditional type 1 diabetes (LADA n=81, RR=0.25, 95% CI: 0.11-0.60; type 1 diabetes, n=18, RR=0.17, 95% Cl: 0.04-0.73). Conclusions/interpretations. The results indicate that nicotine influences autoimmune processes in human diabetes.

Carrera MRA; Kaufmann GF; Mee JM; Meijler MM; Koob GF; Janda KD. Treating cocaine addiction with viruses. Proceedings of the National Academy of Sciences 101(28): 10416-10421, 2004. (45 refs.)

Cocaine addiction continues to be a major health and social problem in the United States and other countries. Currently used pharmacological agents for treating cocaine abuse have proved inadequate, leaving few treatment options. An alternative is to use protein-based therapeutics that can eliminate the load of cocaine, thereby attenuating its effects. This approach is especially attractive because the therapeutic agents exert no pharmacodynamic action of their own and therefore have little potential for side effects. The effectiveness of these agents, however, is limited by their inability to act directly within the CNS. Bacteriophage have the capacity to penetrate the CNS when administered intranasally. Here, a method is presented for engineering filamentous bacteriophage to display cocaine-binding proteins on its surface that sequester cocaine in the brain. These antibody-displaying constructs were examined by using a locomotor activity rodent model to assess the ability of the phage-displayed proteins to block the psychoactive effects of cocaine. Results presented demonstrate a strategy in the continuing efforts to find effective treatments for cocaine addiction and suggest the application of this protein-based treatment for other drug abuse syndromes.

Choudhry MA; Rana SN; Kavanaugh MJ; Kovacs EJ; Gamelli RL; Sayeed MM. Impaired intestinal immunity and barrier function: A cause for enhanced bacterial translocation in alcohol intoxication and burn injury. Alcohol 33(3): 199-208, 2004. (121 refs.)

Alcohol intoxication is being recognized increasingly as the major factor in pathogenesis after burn injury. Findings from multiple studies support the suggestion that, in comparison with burn-injured patients who sustained injury in the absence of alcohol intoxication, burn-injured patients who sustained injury under the influence of alcohol exhibit higher rates of infection and are more likely to die. Thus, infection becomes the primary cause of death in burn-injured patients. Because the intestine is considered to be a major source of bacteria, studies in experimental animals have been designed to examine whether alcohol intoxication before burn injury enhances bacterial translocation from the intestine. Results of these studies have shown a several-fold increase in bacterial translocation from the intestine in the group of animals receiving combined insult of alcohol intoxication and burn injury compared with findings for the groups receiving either insult alone. Alcohol intoxication and burn injury independent of each other have also been shown to cause an increase in bacterial translocation. The gastrointestinal tract normally maintains a physical mucosal and immunologic barrier that provides an effective defense in keeping bacteria within the intestinal lumen. However, in injury conditions these defense mechanisms are impaired. Intestinal bacteria consequently gain access to extraintestinal sites. Intestine-derived bacteria are implicated in causing systemic infection and in subsequent multiple organ dysfunction in both immunocompromised patients and patients with injury, such as burn and trauma. In this article, we discuss three potential mechanisms that are likely to contribute to the increase in bacterial translocation in alcohol intoxication and burn injury: (1) increase in bacterial growth in the intestine, (2) physical disruption of mucosal barrier of the intestine, and (3) suppression of the immune defense in the intestine.

Cristiani SA; Pukay-Martin ND; Bornstein RA. Marijuana use and cognitive function in HIV-infected people. Journal of Neuropsychiatry and Clinical Neurosciences 16(3): 330-335, 2004. (27 refs.)

The effect of marijuana use on cognitive function is controversial. Although marijuana use is common in HIV-infected individuals for recreational and medicinal purposes, there have been no studies of the impact of marijuana on cognitive function in these subjects. Marijuana also has known immunologic effects, which increases the relevance in HIV-infected patients. We examined the interaction of HIV disease-stage and marijuana use in 282 subjects, stratified by disease stage and frequency of marijuana use. After controlling for the effects of depression, anxiety, and alcohol use, a significant interaction was observed on an overall measure of cognitive impairment. The effect of marijuana use was greatest in subjects with symptomatic HIV infection. Further inspection suggested that this effect was due primarily to performance on memory tasks. These data suggest that although there is minimal impact of marijuana on uninfected individuals or those at early stages of HIV infection, there is a synergistic effect of HIV and marijuana use in patients with advanced HIV disease. This is consistent with other data suggesting that the subtle effects of some conditions may become more manifest in the setting of immunocompromise

Croxford JL; Yamamura T. Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases? (review). Journal of Neuroimmunology 166(1-2): 3-18, 2005. (186 refs.)

Since the discovery of the cannabinoid receptors and their endogenous ligands, significant advances have been made in studying the physiological function of the endocannabinoid system. The presence of cannabinoid receptors on cells of the immune system and anecdotal and historical evidence suggesting that cannabis use has potent immuno-modulatory effects, has led to research directed at understanding the function and role of these receptors within the context of immunological cellular function. Studies from chronic cannabis smokers have provided much of the evidence for immunomodulatory effects of cannabis in humans, and animal and in vitro studies of immune cells such as T cells and macrophages have also provided important evidence. Cannabinoids can modulate both the function and secretion of cytokines from immune cells. Therefore, cannabinoids may be considered for treatment of inflammatory disease. This review article will highlight recent research on cannabinoids and how they interact with the immune system and also their potential use as therapeutic agents for a number of inflammatory disorders.

De Bie J; Robaeys G; Buntinx F. Hepatitis C, interferon alpha and psychiatric co-morbidity in intravenous drug users (IVDU): Guidelines for clinical practice. Acta Gastro-enterologica Belgica 68(1): 68-80, 2005. (97 refs.)

The evidence regarding the co-morbidity of chronic hepatitis C, psychiatric illness and intravenous drug abuse is reviewed from the literature. Also the occurrence and the treatment of psychiatric side effects during treatment with interferon in patients with a history of drug abuse are reviewed. There is insufficient evidence for a specific hepatitis C induced depression or fatigue, but a direct link between hepatitis C and cerebral dysfunction is not excluded. Immune system activation rather than drug use may explain cerebral symptoms. In HCV positive substance users anxiety and depression are more prevalent than in HCV negative substance users. During treatment with regular or pegylated (PEG) interferon depression is a frequent side effect (ca 30%) and occurs independently from pre-existing psychiatric disorders or drug abuse. A history of drug abuse per se does not increase the risk of depression as a side effect of interferon treatment. It is extremely important to monitor symptoms of depression in the early weeks of treatment and to start antidepressant treatment as early as possible. Antidepressants should be continued throughout the interferon treatment period. There are insufficient data to assess these situations in which preventive antidepressant treatment should be started before interferon treatment. Clinical judgment can, however, lead to preventive antidepressant treatment, even at subclinical levels of depression. A cut off score of > 10 on the Beck Depression Inventory before interferon treatment is associated with a higher risk of depression during treatment. Both selective serotonin reuptake inhibitors and other classes of antidepressants can be used.

Dewey WL, ed. Problems of Drug Dependence, 2003: Proceedings of the 65th Annual Scientific Meeting. NIDA Research Monograph 184. Rockville MD: National Institute on Drug Abuse, 2004. (Chapter refs.)

This volume represents the proceedings of The 65th Annual Scientific Meeting of The College on Problems of Drug Dependence. The report includes presented papers, poster sessions, and oral communications. There are reports of seventeen symposia that focus on the following topics: understanding the pathway from use to addiction; immunotherapies for substance abuse; drug reward in humans, the role of dopamine; sex differences in the addicted brain, neuroimaging studies of cocaine and alcohol-dependent men and women; current knowledge about exposure to buprenorphine during pregnancy and lactation; vocational rehabilitation models of substance users; controversies in the pharmacology and toxicology of substituted amphetamines; conceptions of drug dependence, theories, science and policy; changing proteins; changing brain; nicotine, addiction and immunomodulation; neuro-aids, and the role of recreational drugs; effectiveness of adolescent substance abuse treatment; abuse potential.

Dhillon NK; Williams R; Peng F; Tsai YJ; Dhillon S; Nicolay B et al. Cocaine-mediated enhancement of virus replication in macrophages: Implications for human immunodeficiency virus-associated dementia. Journal of Neurovirology 13(6): 483-495, 2007. (58 refs.)

Injection drug use has been recognized as a major risk factor for acquired immunodeficiency syndrome (AIDS) from the outset of the epidemic. Cocaine, one of the most widely abused drugs in the United States, can both impair the functions of macrophages and CD4(+) lymphocytes and also activate human immunodeficiency virus (HIV)-1 expression in these cells. Because the brain is the target organ for both cocaine and HIV, the objective of the present study was to explore the effects of cocaine on virus replication in macrophages, the target cells for the virus in the central nervous system (CNS). Cocaine markedly enhanced virus production in simian human immunodeficiency virus (SHIV)-infected monocyte-derived macrophages (MDMs) and in U1 cells, a chronically infected promonocytic cell line as monitored by enzyme-linked immunosorbent assay (ELISA) and immunocytochemistry. Cocaine treatment also resulted in the activation of nuclear factor (NF)-kappa B and transcriptional activation of the HIV-LTR (long terminal repeat) gag-GFP (green fluorescent protein). Analyses of chemokines in cocaine-treated macrophages by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Luminex assays suggested increased expression of interleukin (IL)-10, a cytokine that is known to promote HIV replication in MDMs. In addition to enhancing IL-10 expression, cocaine also caused an up-regulation of the macrophage activation marker, human leukocyte antigen (HLA)-DR, in MDMs. The synergistic effect of cocaine on virus replication and its enhancement of host activation markers suggest that cocaine functions at multiple pathways to accelerate HIV-associated dementia (HAD).

Dolan KA. Quitter's aid. Forbes 174(2): 180, 2004

A new approach to nicotine addiction is emerging: an experimental vaccine to block the nicotine from entering the brain to deliver its pleasurable rush. Nicotine floats around the blood like any other foreign antigen, but its molecules are small enough both to slip past the blood-brain barrier and elude the immune system's policing antibody cells. A nicotine vaccine would work like other vaccines, provoking the body into producing targeted antibodies that, in this case, latch onto molecules so they're too big to enter the brain. Several companies are pursuing nicotine vaccines. One NicVax vaccine is being studied. Preliminary quitting rates are due out later this year from its study of 63 smokers who were injected with the vaccine. Efforts date to 1996, when the company came up with a workable vaccine for Staphylococcus aureus, a leading cause of infection in hospitals. Staph molecules are good at eluding the immune system because they're disguised by an abundant coat of sugars. Fattom's solution was to link the sugars to a larger carrier protein, in this case an inactivated bacteria called Pseudomonas. The immune system spots the combination and produces antibodies that then bind to the staph molecules in the body, preventing infection. it was thought the same process would work on other elusive molecules, such as nicotine. Early-stage human trials completed in 2002 have shown that nicotine antibodies are still at measurable levels in the blood for 7 to 14 days after one shot. Side effects such as soreness and redness at the injection point clear up in a few days.

Douglas SD; Camarca M; Xu JH; Durako S; Murphy D; Moscicki B et al. The relationships between substance abuse, psychosocial variables, and natural killer cell enumeration and function in HIV-infected and high-risk uninfected adolescents. AIDS Research and Human Retroviruses 19(5): 399-408, 2003. (45 refs.)

This report examines the relationship between substance use, psychosocial stressors, and natural killer (NK) cell enumeration and function in HIV-infected and high-risk uninfected adolescents. We studied the association of demographic characteristics; self-report measures of alcohol, tobacco, and marijuana use; and self-report measures of psychosocial stressors (depressive symptoms, anxiety) with three immune outcomes: NK (CD3(-)CD16(+)CD56(+)) absolute counts, lytic units per peripheral blood mononuclear cells (PBMCs), and lytic units per NK cell. In addition, we determined the association of HIV disease stage, antiretroviral therapy (ART), CD4(+) T-cell count, and viral load with these outcomes in the subset of HIV-infected adolescents. Methods: This cross-sectional analysis reports on data collected during a longitudinal observational study of adolescents (the REACH Study). A cross-sectional analysis was performed with data from the first visit for each subject that met criteria for concurrent (within 3 days) assessment of NK number and function, substance use, and psychosocial data. The data set represented 501 subjects. Analyses were performed separately for the HIV-seropositive and seronegative adolescents. In the HIV-seronegative population, there were no significant predictors of NK cell count and only female gender was significantly associated with CD3(-)CD16(+)CD56(+) NK lytic units per PBMC. Analysis of the HIV-seronegative cohort also showed that black race was significantly associated with higher lytic units per NK cell. Results: In HIV-seropositive adolescents, we observed an association of female gender with lower NK cell number and lytic units per PBMC, but not with lytic units per NK cells. Current use of one or two antiretroviral drugs was predictive of lower NK numbers. This drug effect was also noted in the functional assay per PBMC but not per NK cell. Increasing worry scores and no marijuana use over the past 3 months were associated with lower functional NK measures per PBMC in HIV-seropositive youth. Laboratory-confirmed recent marijuana use was highly predictive of increased lytic activity calculated per NK cell. These effects were not observed in similar analyses of data from HIV-seronegative adolescents. Depressive symptoms, assessed with an epidemiologic screening tool, were not found to be predictive of NK cell number or function in either the HIV-seronegative or the HIV-seropositive subset. These findings document associations between substance abuse, psychosocial variables, and NK numbers and function in adolescents.

Duryee MJ; Willis MS; Freeman TL; Kuszynski CA; Tuma DJ; Klassen LW et al. Mechanisms of alcohol liver damage: Aldehydes, scavenger receptors, and autoimmunity. (review). Frontiers in Bioscience 9(Supplement S): 3145-3155, 2004. (112 refs.)

While most of the investigations into the causative events in the development of alcoholic liver disease (ALD) have been focused on multiple factors, increasing interest has centered around the possible role of immune mechanisms in the pathogenesis and perpetuation of ALD. This is because many of the clinical features of ALD suggest that immune effector mechanisms may be contributing to liver tissue damage, as evidenced by the detection of circulating autoantibodies, and the presence of CD4+ and CD8+ lymphoid cells in the livers of patients with ALD. One mechanism that has been associated with the development of autoimmune responses is the modification (haptenation or adduction) of liver proteins with aldehydes or other products of oxidative stress. This is because it has been shown that these adducted proteins can induce specific immune responses, to the adduct, the adduct plus protein (conformational antigens), as well as the unmodified parts of the protein. More importantly, it is possible to demonstrate that adducted self-proteins can induce reactivity to the normal self-protein and thereby induce autoimmune responses. Therefore, it is the purpose of this manuscript to outline the mechanism(s) by which these modified self proteins can induce autoimmune reactivity, and thus play a role in the development and/or progression of ALD.

EL-Gohary M; Eid MA. Effect of cannabinoid ingestion (in the form of bhang) on the immune system of high school and university students. Human and Experimental Toxicology 23(3): 149-156, 2004. (37 refs.)

The discovery of cannabinoid receptors in the immune system and a family of endogenous ligands of these receptors provides a basis for understanding the cellular and molecular mechanisms of cannabis-induced immunotoxicity. The present study was conducted on 90 nonsmoker males of high school and university students living in Tanta city of matched age and socioeconomic lifestyle. They were divided into a control group (30 males) and a bhang user group (60 males), which used bhang by eating its sweet juice after boiling with a little water and drying in an oven, 'fola'. The bhang group was divided equally into two subgroups: subgroup 1 used bhang for 6-24 months (average 199 +/- 1.2) and subgroup 2 used bhang for 24-36 months (average 31 +/- 1.7). The immunotoxic effects of using bhang appeared in the form of a significant decrease in serum immunoglobulins (IgG and IgM), and C3 and C4 complement protein concentrations (P < 0.05). In addition, our results demonstrated a significant decrease in the absolute number of functionally different subsets of peripheral blood mononuclear lymphocytes, T and B lymphocytes and natural killer (NK) cells in bhang users as compared to controls (P < 0.05). Moreover, the fatty acid amide hydrolase (FAAH) showed significant decrease in bhang users as compared to controls and in subgroup 2 as compared to subgroup 1 (P < 0.05), indicating that the decrease in FAAH protein level is closely related to the duration of bhang use. Positive correlations were found between FAAH level and the absolute number of mononuclear cells (T, B lymphocytes and NK cells) among bhang user subgroups. The present study is the first study to report on the effect of bhang on complement proteins and immunoglobulins in humans. Our study revealed that bhang-induced immunotoxicity could be attributed to decrease in FAAH protein.

Fingerhood MI. Co-morbid medical disorders. IN: Strain EC; Stitzer ML, eds. The Treatment of Opioid Dependence. Baltimore: Johns Hopkins University Press, 2006. pp. 398-420. (65 refs.)

This chapter focuses on the provision of medical care to individuals receiving opioid agonist medications. It considers the issues related to health maintenance, and the multiple medical complications. Among those with a history of intravenous use, there are special concerns related to the route of administration -- including viruses from needle sharing as well as the soft tissue infections from injecting technique. These problems are not restricted to those involved with opiates, but also common in cocaine users. The chapter begins with an overview of basic primary care, with attention to medical history and physical exam. It then turns of matters related to prescribing, pain management, and drug interactions with methadone, that may have an impact on blood levels or alter methadone's effects. Also specifically addressed are skin and soft tissue infections, HIV/AIDS, sexually transmitted disease, hepatitis, as well as cardiac, pulmonary, renal, neurological, and immunologic complications, and for women concerns related to domestic violence.

Floto RA; Smith KGC. The vagus nerve, macrophages, and nicotine. (editorial). Lancet 361(9363): 1069-1070, 2003. (15 refs.)

Frank J; Witte K; Schrodl W; Schutt C. Chronic alcoholism causes deleterious conditioning of innate immunity. Alcohol and Alcoholism 39(5): 386-392, 2004. (60 refs.)

Aims: To examine the immune consequences of chronic alcoholism in man, in relation to the known association between alcoholism and raised incidence and severity of infections. Methods: In 36 alcoholics without liver disease, at the point of commencing withdrawal from alcohol, the following measures of immune competence were measured: the immunophenotypes of cells, acute phase proteins, the endotoxin-neutralizing capacity (ENC) of the serum, titers of anti-lipopolysaccharide (LPS) antibodies, and ex vivo cytokine inducibility in T cells and monocytes (TNFalpha, IL1beta, IL1RA, IL4, IL6, IL8, IL10 and IL12). The results were compared to those from healthy volunteers (day controls). Measures were repeated after 8-13 days of abstinence. Results: LPS-binding protein (LBP) and soluble CD14 (sCD14) were significantly increased in patients' sera at the outset of withdrawal, whereas reduced titers of anti-LPS IgG (P = 0.012) and a reduced ENC (P = 0.001) were measured. Only ENC rapidly returned to normal values after withdrawal therapy. Cytokine induction with phorbol ester showed no significant alterations in patients' T cells. Patients' monocytes, however, responded to LPS stimulation with enhanced IL1beta-, but reduced TNFalpha- and IL12-production (P = 0.004, P = 0.0042 and P = 0.001, respectively). While IL1- and TNFalpha-responses normalized after the withdrawal period, impairment of the IL12 response persisted throughout the observation period of 2 weeks. Conclusions: Alcoholism results in a prolonged LPS-mediated hypoinflammatory conditioning of the innate but not the adaptive immune system, which is not reversed immediately after withdrawal. This alcohol-induced status of the immune system predisposes to infections and sepsis by blunting initial response to the pathogens.

Friedman H; Pross S; Klein TW. Addictive drugs and their relationship with infectious diseases. (review). FEMS Immunology and Medical Microbiology 47(3): 330-342, 2006. (120 refs.)

The use of drugs of abuse, both recreationally and medicinally, may be related to serious public health concerns. There is a relationship between addictive drugs of abuse such as alcohol and nicotine in cigarette smoke, as well as illegal drugs such as opiates, cocaine and marijuana, and increased susceptibility to infections. The nature and mechanisms of immunomodulation induced by such drugs of abuse are described in this review. The effects of opiates and marijuana, using animal models as well as in vitro studies with immune cells from experimental animals and humans, have shown that immunomodulation induced by these drugs is mainly receptor-mediated, either directly by interaction with specific receptors on immune cells or indirectly by reaction with similar receptors on cells of the nervous system. Similar studies also show that cocaine and nicotine have marked immunomodulatory effects, which are mainly receptor-mediated. Both cocaine, an illegal drug, and nicotine, a widely used legal addictive component of cigarettes, are markedly immunomodulatory and increase susceptibility to infection. The nature and mechanism of immunomodulation induced by alcohol, the most widely used addictive substance of abuse, are similar but immunomodulatory effects, although not receptor-mediated. The many research studies on the effects of these drugs on immunity and increased susceptibility to infectious diseases, including AIDS, are providing a better understanding of the complex interactions between immunity, infections and substance abuse.

Gallus S; Giordano L; Altieri A; Talamini R; La Vecchia C. Cigarette smoking and risk of Hodgkin's disease. European Journal of Cancer Prevention 13(2): 143-144, 2004. (11 refs.)

The role of cigarette smoking on the risk of Hodgkin's disease remains controversial. To provide further information on the issue, we analysed data of a case-control study from northern Italy. The cases were 158 patients with incident histologically confirmed Hodgkin's disease, and the controls were 316 patients, frequency-matched to the cases by age, sex and study centre, and admitted to the same network of hospitals for acute, non-neoplastic, non-alcohol- or non-tobacco-related conditions. Compared with those who had never smoked, the multivariate odds ratio was 0.54 for former and 0.85 for current smokers. No trend in risk was found for either the number of cigarettes smoked or the duration of consumption. None of the estimates, or the corresponding trends in risk, was statistically significant Our results are consistent with those of several studies indicating no direct association between cigarette smoking and risk of Hodgkin's disease.

Gamble L; Mason CM; Nelson S. The effects of alcohol on immunity and bacterial infection in the lung. (review). Medecine et Maladies Infectieuses 36(2): 72-77, 2006. (39 refs.)

When faced with invading pathogens that can lead to infection, patients must mount an effective and appropriate immune response. Altered immune function in patients who abuse alcohol has long been described in the medical literature. The alcohol-consuming host is particularly prone to infections in the lung, including bacterial pneumonia and tuberculosis. Over the last several decades, there has been increased interest in the immune mechanisms that underlie the increased risk of infection observed in this population. This article will review the basic immunology involved in the host response to an infection and then describe how alcohol disrupts many of these immune mechanisms. It will further provide an overview of lung infections which have been linked to alcohol abuse, and finally, it will address the evolving therapeutic approaches of the immune system that are being advanced to assist in caring for immuno suppressed hosts.

Gauthier TW; Manar MH; Brown LAS. Is maternal alcohol use a risk factor for early-onset sepsis in premature newborns? Alcohol 33(2): 139-145, 2004. (55 refs.)

Because chronic alcohol abuse alters immune defenses and increases infection in adults, we tested the hypothesis that maternal alcohol use during pregnancy would increase the risk of sepsis in very low birth weight (VLBW) premature newborns. We performed a case-controlled analysis of VLBW newborns born at Grady Memorial Hospital (Atlanta, GA). Alcohol exposure, as the predictive variable, was assessed by maternal self-report. The outcome variables were early-onset and multiple late-onset sepsis. Univariate analysis with Fisher exact test and multivariate analysis with the use of binary logistic regression were performed. Early-onset sepsis was 15-fold higher in the alcohol-exposed group (n = 20) compared with findings for the matched control group (n = 168) [alcohol-exposed group, 10%, vs. control group, 0.6%: odds ratio (OR) 6.8 (95% confidence interval [CI], 2.7-17.1), P � .05]. Early-onset sepsis in the alcohol + cocaine-exposed group (n = 64) did not differ from findings for the control group. The prevalence of multiple late-onset sepsis did not differ among the exposure groups. Logistic regression analysis, controlling for chorioamnionitis and premature prolonged rupture of membranes, demonstrated an independent, increased risk of early-onset sepsis with alcohol exposure [OR 16 (95% CI, 1.2-210), P � .05]. We conclude that alcohol exposure significantly increased the risk of early-onset sepsis in this group of VLBW newborns. The effects of maternal alcohol abuse during pregnancy on the risk of infection in the VLBW newborn require further analysis.

Ghaussy NO; Sibbitt WL; Bankhurst AD; Qualls CR. Cigarette smoking and disease activity in systemic lupus erythematosus. Journal of Rheumatology 30(6): 1215-1221, 2003. (62 refs.)

Objective. To investigate the effect of cigarette smoking on disease activity and cumulative organ damage in systemic lupus erythematosus (SLE). Methods. Extensive clinical and demographic variables, including current and previous cigarette smoking, were collected from 111 SLE patients using a detailed interview-administered questionnaire. Disease activity was estimated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Cumulative organ damage was measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR). Smoking status was correlated with disease activity and cumulative organ damage, while statistically adjusting for the individual effects of potentially confounding demographic and clinical variables using analysis of variance followed by Fisher's least significant difference method. Results. Current smokers demonstrated significantly higher (p < 0.001) SLEDAI scores (15.6 +/- 7.8) than ex-smokers (9.63 +/- 6.00), and never smokers (9.03 +/- 5.75). This association remained significant (p = 0.001) after adjusting for all covariates, including ethnicity, education level, income level, alcohol use, age of onset of SLE, current age, mean duration of SLE, marital status, and hydroxychloroquine therapy. Current smokers also demonstrated significantly (p = 0.003) higher scores for both the neurological and non-neurological components of SLEDAI There was no significant difference in the SLICC/ACR scores across the various smoking groups, although there was a trend for more severe disease in current smokers. Conclusion. Cigarette smoking is associated with increased disease activity in SLE. These data further establish the association of SLE with cigarette smoking, and suggest that individuals with SLE should avoid all exposure to tobacco products.

Goforth HW; Lupash DP; Brown ME; Tan J; Fernandez F. Role of alcohol and substances of abuse in the immunomodulation of human immunodeficiency virus disease: A review. Addictive Disorders and Their Treatment 3(4): 174-182, 2004. (45 refs.)

A significant body of evidence links the continued spread of infection with human immunodeficiency virus (HIV) with substance abuse. Some studies have shown changes in behavior which leave individuals at risk for acquiring and spreading HIV infection. Moreover, alcohol and illicit drugs are known to have a direct and toxic effect on the immune system, increase susceptibility to opportunistic infections, inadequate response to antiretroviral therapies, and exacerbate or uncover cognitive inefficiency. This review focuses on the emerging data of the immunomodulatory and toxic effects of alcohol and illicit drugs as well as nicotine. The use of these agents presents a special challenge because of the deleterious effects on HIV-related disease and its progression to fully developed AIDS. There is an urgent need to recognize and incorporate this knowledge into collaborative care between medicine, infectious disease, addiction medicine and mental health professionals to inform treatment and management decisions.

Gonzalez-Quintela A; Vidal C; Gude F. Alcohol, IgE and allergy. (review). Addiction Biology 9(3/4): 195-204, 2004. (91 refs.)

Alcoholic drinks are involved in a variety of hypersensitivity reactions. These include flushing syndrome, anaphylactoid reactions (urticaria/angioedema and even shock), as well as the triggering of asthma, food allergy or exercise-induced anaphylaxis in susceptible subjects. In addition, there is increasing evidence that alcohol intake may play a role as a promoter of the development of immunoglobulin-E (IgE)-mediated hypersensitivity to different allergens. It seems clear that alcohol intake (alcohol abuse and even moderate alcohol consumption) is associated with increased total serum IgE levels. Similarly, alcohol intake may be associated with allergic (IgE-mediated) sensitization to environmental allergens. The clinical significance of these facts is probably moderate. The mechanisms by which alcohol can influence IgE responses are not entirely known, but further developments in this area could increase the understanding of both allergic diseases and alcohol-induced alterations in the immune system.

Gorelick DA; Gardner EL; Xi ZX. Agents in development for the management of cocaine abuse. (review). Drugs 64(14): 1547-1573, 2004. (252 refs.)

Cocaine abuse is a serious health problem in many areas of the world, yet there are no proven effective medications for the treatment of cocaine dependence. Preclinical studies suggest that the reinforcing effect of cocaine that promotes its abuse is mediated by blockade of the presynaptic dopamine transporter. This results in increased dopamine activity in the mesolimbic or meso-accumbens dopamine reward system of brain. Development of new medications to treat cocaine dependence has focused on manipulation of this dopamine system, either by direct action on dopamine binding sites (transporter or receptors) or indirectly by affecting other neurotransmitter systems that modulate the dopamine system. In principle, a medication could act via one of three mechanisms: (i) as a substitute for cocaine by producing similar dopamine effects; (ii) as a cocaine antagonist by blocking the binding of cocaine to the dopamine transporter; or (iii) as a modulator of cocaine effects by acting at other than the cocaine binding site. The US National Institute on Drug Abuse has a Clinical Research Efficacy Screening Trial (CREST) programme to rapidly screen existing medications. CREST identified four medications warranting phase II controlled clinical trials: cabergoline, reserpine, sertraline and tiagabine. In addition, disulfiram and selegiline (deprenyl) have been effective and well tolerated in phase II trials. However, selegiline was found ineffective in a recent phase III trial. Promising existing medications probably act via the first or third aforementioned mechanisms. Sustained-release formulations of stimulants such as methylphenidate and amfetamine (amphetamine) have shown promise in a stimulant substitution approach. Disulfiram and selegiline increase brain dopamine concentrations by inhibition of dopamine-catabolising enzymes (dopamine-p-hydroxylase and monoamine oxidase B, respectively). Cabergoline is a direct dopamine receptor agonist, while reserpine depletes presynaptic stores of dopamine (as well as norepinephrine and serotonin). Sertraline, baclofen and vigabatrin indirectly reduce dopamine activity by increasing activity of neurotransmitters (serotonin and GABA) that inhibit dopamine activity. Promising new medications act via the second or third aforementioned mechanisms. Vanoxerine is a long-acting inhibitor of the dopamine transporter which blocks cocaine binding and reduces cocaine self-administration in animals. Two dopamine receptor ligands that reduce cocaine self-administration in animals are also undergoing phase I human safety trials. Adrogolide is a selective dopamine D-1 receptor agonist; BP 897 is a D-3 receptor partial agonist. A pharmacokinetic approach to treatment would block the entry of cocaine into the brain or enhance its catabolism so that less cocaine reached its site of action. This is being explored in animals using the natural cocaine-metabolising enzyme butyrylcholinesterase (or recombinant versions with enhanced capabilities), catalytic antibodies, and passive or active immunisation to produce anti-cocaine binding antibodies. A recent phase I trial of a 'cocaine vaccine' found it to be well tolerated and producing detectable levels of anti-cocaine antibodies for up to 9 months after immunisation.

Goto Y; O'Malley C; Fanning NF; Wang J; Redmond HP; Shorten GD. Benzodiazepines inhibit the rate of neutrophil apoptosis. Irish Journal of Medical Science 172(4): 191-194, 2003. (24 refs.)

Background Benzodiazepines, which are commonly administered perioperatively, can depress immune function. Neutrophil apoptosis plays a central role in the regulation of inflammation. This is particularly important during and after surgery. Aim To examine the effects of benzodiazepines (midazolam and diazepam) on neutrophil apoptosis. Methods: Venous blood samples were withdrawn from patients scheduled to undergo elective surgery, (a) immediately prior to, and 10 minutes after administration of midazolam 0.2mg/kg intravenously (n=11) and (b) immediately prior to, and 60 minutes after administration of diazepam 10mg po (n=10). Neutrophil apoptosis was measured by Annexin VFITC after 1 and 12 hours in culture.Results The percentage of apoptotic cells was significantly less after midazolam at 12% (11.9) hours in culture compared to pre-midazolam 29.7% (13.3) (p<0.05). After diazepam, the rates of neutrophil apoptosis were also significantly less after 12 hours in culture (p<0.05). Conclusion: Administration of benzodiazepines in clinically relevant doses inhibits neutrophil apoptosis. In the perioperative period, this may influence the inflammatory response to surgery.

Hall W; Carter L. Ethical issues in using a cocaine vaccine to treat and prevent cocaine abuse and dependence. Journal of Medical Ethics 30(4): 337-340, 2004. (35 refs.)

A "cocaine vaccine'' is a promising immunotherapeutic approach to treating cocaine dependence which induces the immune system to form antibodies that prevent cocaine from crossing the blood brain barrier to act on receptor sites in the brain. Studies in rats show that cocaine antibodies block cocaine from reaching the brain and prevent the reinstatement of cocaine self administration. A successful phase 1 trial of a human cocaine vaccine has been reported. The most promising application of a cocaine vaccine is to prevent relapse to dependence in abstinent users who voluntarily enter treatment. Any use of a vaccine to treat cocaine addicts under legal coercion raises major ethical issues. If this is done at all, it should be carefully trialled first, and only after considerable clinical experience has been obtained in using the vaccine to treat voluntary patients. There will need to be an informed community debate about what role, if any, a cocaine vaccine may have as a way of preventing cocaine addiction in children and adolescents.

Halpern JH; Sholar MB; Glowacki J; Mello NK; Mendelson JH; Siegel AJ. Diminished interleukin-6 response to proinflammatory challenge in men and women after intravenous cocaine administration. Journal of Clinical Endocrinology and Metabolism 88(3): 1188-1193, 2003. (47 refs.)

Cocaine abuse is associated with increased rates of infections, including human immunodeficiency virus, and cocaine has immunomodulatory effects in experimental animal and cellular models. When challenged by antigens, tissues release cytokine polypeptides that signal a complex balance of cellular and humoral immune responses. Placement of indwelling venous catheters also leads to surrounding tissue inflammation, mediated partially by local production and release of the proinflammatory cytokine, IL-6. Thus, catheter placement provides a model for examination of cocaine's immunological effects. Thirty healthy men and women with a history of cocaine use participated in this study of neuroendocrine and immunological responses to iv injection of 0.4 mg/kg cocaine or saline placebo. After injection, blood samples were collected from the antecubital vein of the opposite arm via anindwelling venous catheter at 2,4,8,12,16,20,30,40,60,80,120, 180, and 240 min. Cocaine, ACTH, cortisol, and dehydroepiandrosterone concentrations peaked at 8, 12, 40, and 20 min, respectively. Stimulation of IL-6 at 240 min was markedly reduced in subjects receiving cocaine compared with subjects receiving placebo (3.85 +/- 0.49 vs. 11.64 +/- 2.21 pg/ml; P = 0.0019, by two-tailed t test). Gender and menstrual cycle phase did not significantly influence most endocrine or IL-6 measures, although the small number of subjects limits the power of these comparisons. Because cocaine stimulates the hypothalamic-pituitary-adrenal axis, IL-6 suppression may be a consequence of corticosteroid release. Cocaine-induced suppression of proinflammatory IL-6 may mediate impaired host defenses to infections.

Hancox RJ; Welch D; Poulton R; Taylor DR; McLachlan CR; Greene JM et al. Cigarette smoking and allergic sensitization: A 32-year population-based cohort study. Journal of Allergy and Clinical Immunology 121(1): 38-42, 2008. (33 refs.)

Background: Cigarette smoke has immunosuppressant effects, but its effect on allergic sensitization is unclear. Objective: To investigate associations between parental and personal smoking and skin prick tests (SPTs) for atopy in a population-based birth cohort of 1037 participants followed to adulthood. Methods: Parental history of atopic disease, parental smoking, and personal smoking were obtained at multiple assessments between birth and age 32 years. Atopy was assessed by SPTs for 11 common inhaled allergens at ages 13 and 32 years. Results: Children of atopic parents were less likely to have positive SPTs at age 13 years if either parent smoked (odds ratio, 0.55; P =.009). This association was not significant after adjusting for breast-feeding history, number of siblings, and childhood socioeconomic status. Subjects with atopic parents were also less likely to develop positive results to SPTs between ages 13 and 32 years if they smoked themselves (odds ratio, 0.18; P <.001). This reduction in risk remained significant after adjusting for multiple potential confounding factors. Neither parental nor personal smoking was significantly associated with allergic sensitization among subjects whose parents did not have a history of atopic disease. Few of those with positive SPT results at age 13 years had negative tests at age 32 years, and there was no evidence that this was influenced by smoking. Conclusion: Personal and parental smoking is associated with a reduced risk of allergic sensitization in people with a family history of atopy.

Harwood HJ; Myers TG, eds. New Treatments for Addiction: Behavioural, Ethical, Legal and Social Questions. Washington DC: National Academies Press, 2004. (Chapter refs.)

In developing this report the National Academy of Science assembled leading addiction researchers and policy analysts to anticipate the behavioural, ethical, legal and social questions that will arise if promising new immunological treatments (drug vaccines) and depot forms of opioid antagonists are approved for the treatment of addiction to nicotine and illicit drugs. The book includes a 53-page overview of the consensus statement and the accompanying, commissioned background papers. The report begins by describing the immunological rationale of drug vaccines (Pentel). Drug vaccines induce the immune system to form antibodies that bind to the drug (e.g. nicotine) by combining a protein molecule with the drug to provoke an immune response. The antibodydrug complex binds to the drug to form molecules that are too large to cross the bloodbrain barrier, thereby intercepting the drug in the bloodstream before it can act on receptor sites in the brain. Animal studies have provided evidence for the feasibility of using vaccines to block drug effects and interrupt self-administration. Human trials are under way for cocaine and nicotine vaccines so the current volume is a very timely one. Among the range of issues addressed are -- the regulatory and economic challenges in getting drug vaccines approved by the FDA (Kosten & Kranzler); lessons from past failures to introduce new pharmacotherapies into the specialist addiction treatment system (Wood & McNicholas) or the primary health-care setting in the United States (Thomas and McCarty); legal issues raised by the use of vaccines and depot drugs under legal coercion within the criminal justice system (Ridgely et al.) and the probable 'off label' use of vaccines by parents eager to prevent their children and adolescents from becoming addicted to drugs (Miller & Klanica); ethical issues raised by researching and using drug vaccines (Murray); and the probable costs and benefits of drug vaccines (Kleiman). MacCoun makes some plausible projections about the unanticipated consequences of using drug vaccines to treat addiction, which include: addicts using other drugs or larger doses to overcome the immune blockade, thereby increasing overdose risk; risk compensation if addiction comes to be seen as an easily treated minor inconvenience; increased crime to fund more expensive drug use; and a possible arms race between vaccine makers and black market entrepreneurs.

Hasman A; Holm S. Nicotine conjugate vaccine: Is there a right to a smoking future? Journal of Medical Ethics 30(4): 344-345, 2004. (7 refs.)

Tobacco consumption is believed to be one of the world's greatest preventable health problems. According to the World Health Organisation, 1.1 billion people worldwide are addicted to nicotine with tobacco causing an estimated four million premature deaths every year. The development of a nicotine conjugate vaccine suggests that immunisation may hold promise as a future therapeutic and preventive strategy for tobacco smoking and nicotine addiction. Allowing parents to immunise their children against smoking could be an infringement of children's right to an open future, however, and is not ethically unproblematic.

Helliwell RJA; Chamley LW; Blake-Palmer K; Mitchell MD; Wu J; Kearn CS. Characterization of the endocannabinoid system in early human pregnancy. Journal of Clinical Endocrinology and Metabolism 89(10): 5168 -5174, 2004. (26 refs.)

In recent years, it has been demonstrated that high circulating levels of the endogenous cannabinoid anandamide, resulting from low expression of its metabolizing enzyme fatty acid amide hydrolase (FAAH), may contribute to spontaneous miscarriage and poor outcome in women undergoing in vitro fertilization. The site of action of this compound, however, has not been determined. In this study, we examined the distribution of the cannabinoid receptors, CB1 and CB2, and the endocannabinoid-metabolizing enzyme FAAH in first trimester human placenta. Here, we show that FAAH is expressed throughout the human first trimester placenta, in extravillous trophoblast columns, villous cytotrophoblasts, syncytiotrophoblasts, and macrophages. Furthermore, FAAH mRNA levels appear to be regulated during gestation, with levels peaking at 11 wk before declining again. The immune system-associated cannabinoid CB2 receptors were localized only to placental macrophages. Interestingly, the cannabinoid receptor CB1 was not identified in first trimester placenta despite having previously been shown to be present in placental tissues at term. These findings suggest that the placenta may form a barrier preventing maternal-fetal transfer of anandamide and/or modulate local levels of anandamide by regulation of FAAH expression with gestation.

Horrigan LA; Kelly JP; Connor TJ. Immunomodulatory effects of caffeine: Friend or foe? (review). Pharmacology & Therapeutics 111(3): 877-892, 2006. (135 refs.)

Caffeine is a member of the methylxanthine family of drugs, and is the most widely consumed behaviourally active substance in the western world. This article is focused on the impact of caffeine on immune function. In this regard, a number of in vitro and in vivo studies have demonstrated that caffeine modulates both innate and adaptive immune responses. For instance studies indicate that caffeine and its major metabolite paraxanthine suppress neutrophil and monocyte chemotaxis, and also suppress production of the pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha from human blood. Caffeine has also been reported to suppress human lymphocyte function as indicated by reduced T-cell proliferation and impaired production of Th-1(interleukin [IL]-2 and interferon [IFN]-gamma), Th-2 (IL-4, IL-5) and Th-3 (IL-10) cytokines. Studies also indicate that caffeine suppresses antibody production. The evidence suggests that at least some of the immunomodulatory actions of caffeine are mediated via inhibition of cyclic adenosine monophosphate (cAMP)-phosphodiesterase (PDE), and consequential increase in intracellular cAMP concentrations. Overall, these studies indicate that caffeine, like other members of the methylxanthine family, is largely anti-inflammatory in nature, and based on the pharmacokinetics of caffeine, we suggest that many of its immunomodulatory effects occur at concentrations that are relevant to normal human consumption. Finally, the potential of caffeine-induced immunomodulation to significantly impact upon health and well-being are discussed.

Imhof A; Koenig W. Alcohol inflammation and coronary heart disease. (review). Addiction Biology 8(3): 271-277, 2003. (66 refs.)

This overview summarizes the experimental and epidemiological evidence linking alcohol consumption and the immune system. It focuses on findings supporting the notion that moderate alcohol consumption exerts anti-inflammatory effects which may explain, at least in part, the reduced risk of coronary heart disease morbidity and mortality in these subjects. Alcohol consumption has been shown consistently to be associated with all-cause mortality in a F- or U-shaped manner. This is due primarily to reduced risk of coronary heart disease (CHD) mortality among moderate consumers of alcohol compared to abstainers and heavy drinkers. Several mechanisms have been suggested by which moderate alcohol consumption could lower risk of CHD. However, changes in lipids, such as increased HDL cholesterol and apolipoprotein A I or a favourable haemostatic profile, can only partly explain the beneficial effects. Recently, anti-inflammatory effects of moderate intake of alcohol have been considered as an additional possible explanation, as inflammation has a fundamental role in the initiation, progression and the thrombotic complications of atherosclerosis.

Islam SN; Hossain KJ; Kamal M; Ahsan M. Serum immunoglobulins and white blood cells status of drug addicts: influence of illicit drugs and sex habit. Addiction Biology 9(1): 27-33, 2004. (43 refs.)

The aim of this study was to investigate the serum immunoglobulins and white blood cells status of drug addicts and to assess the extent of influence of drug habit and sexual practice on the immune components. The study was conducted among 253 male drug addicts and 100 non-addict controls of aged 18-45 years. An enzyme-linked immunosorbent assay (ELISA) was employed to analyse the serum immunoglobulin concentrations. White blood cells pro. le was estimated by counting 200 cells. Results showed a significant increase (p<0.03) of serum IgG, IgA and IgM in the drug addicts (6.93&PLUSMN;1.53 g/l, 2.90&PLUSMN;1.13 g/l and 1.72&PLUSMN;0.73 g/l, respectively) compared to those in the cohort controls (6.52&PLUSMN;1.05 g/l, 2.61&PLUSMN;0.83 g/l and 1.52&PLUSMN;0.59 g/l, respectively). A significant (p=0.00) decrease of peripheral lymphocytes (51.8&PLUSMN;15.2 vs. 71.9&PLUSMN;11.5) was noted in the drug addicts. Monocytes (8.3&PLUSMN;4.9), neutrophils (128.2&PLUSMN;18.9) and eosinophils (11.4&PLUSMN;5.8) were found to be increased in the drug addicts against those in the controls (5.2&PLUSMN;2.5, 113.2&PLUSMN;13.0 and 9.6&PLUSMN;5.8, respectively). Multiple drug abuse for longer period had resulted in a significant (p<0.05) decrease of serum immunoglobulins and lymphocytes. The longer period of addiction had also made a significant (p<0.05) decrease of eosinophils (p=0.05) and an increase of monocytes and neutrophils. Sex with multiple sexual partners had shown a significant (p<0.01) decrease of serum immunoglobulins and eosinophils.

Kantak KM. Vaccines against drugs of abuse - A viable treatment option? Drugs 63(4): 341-352, 2003. (63 refs.)

Drug addiction is a chronically relapsing brain disorder. There is an urgent need for new treatment options for this disease because the relapse rate among drug abusers seeking treatment is quite high. During the past decade, many groups have explored the feasibility of using vaccines directed against drugs of abuse as a means of eliminating illicit drug use as well as drug overdose and neurotoxicity. Vaccines work by inducing drug-specific antibodies in the bloodstream that bind to the drug of abuse and prevent its entry into the brain. The majority of work in this area has been conducted with vaccines and antibodies directed against cocaine and nicotine. On the basis of preclinical work, vaccines for cocaine and nicotine are now in clinical trials because they can offer long-term protection with minimal treatment compliance. In addition, vaccines and antibodies for phencyclidine, methamphetamine and heroin abuse are currently under development. An underlying theme in this research is the need for high concentrations of circulating drug-specific antibodies to reduce drug-seeking and drug-taking behaviour when the drug is repeatedly available, especially in high doses. Although vaccines against drugs of abuse may become a viable treatment option, there are several drawbacks that need to be considered. These include: (i) a lack of protection against a structurally dissimilar drug that produces the same effects as the drug of choice; (ii) a lack of an effect on drug craving that predisposes an addict to relapse; and (iii) tremendous individual variability in antibody formation. Forced or coerced vaccination is not likely to work from a scientific perspective, and also carries serious legal and ethical concerns. All things considered, vaccination against a drug of abuse is likely to work best with individuals who are highly motivated to quit using drugs altogether and as part of a comprehensive treatment programme. As such, the medical treatment of drug abuse will not be radically different from treatment of other chronic diseases.

Katona S; Kaminski E; Sanders H; Zajicek J. Cannabinoid influence on cytokine profile in multiple sclerosis. Clinical and Experimental Immunology 140(3): 580-585, 2005. (22 refs.)

Cannabinoids have been suggested as possessing immunomodulatory properties, and cannabinoid receptors are present on leucocytes. Clinically, there is some evidence that cannabinoids may be therapeutically useful in treating multiple sclerosis, which is generally believed to be an autoimmune condition. This paper reports data derived from the Cannabinoids in MS (CAMS) study, which was the largest randomized controlled trial yet conducted to evaluate the therapeutic efficacy of cannabinoids. We found no evidence for cannabinoid influence on serum levels of interferon (IFN)-gamma, interleukin (IL)-10, IL-12 or C-reactive protein as measured using enzyme-linked immunosorbent assay (ELISA), in comparison to control values. Mitogenic stimulation experiments also failed to demonstrate any significant reduction in percentage of CD3(+), IFN-gamma producing cells after exposure to cannabinoids in vivo, although numbers were small. Further work is needed to establish the functional significance of cannabinoid receptors on immune cells.

Kim SH; Ensunsa JL; Zhu QY; Kim JS; Shin HS; Keen CL. An 18-month follow-up study on the influence of smoking on blood antioxidant status of teenage girls in comparison with adult male smokers in Korea. Nutrition 20(5): 437-444, 2004. (29 refs.)

OBJECTIVES: The influence of cigarette smoking on blood antioxidant status in teenage girls with a history of short-term smoking was followed over 18 mo. METHODS: Data obtained from female senior high school students (ages 14 to 18 y) in Korea were compared with data obtained from adult male smokers (ages 36 to 51 y) with a long history of smoking and living in the same geographic areas as the teenage subjects. A snicker was a person who had smoked at least three cigarettes a day for at least 1 y for teenagers (n = 35) or at least 10 cigarettes a day for at least 13 y for adults (n = 20). Serum, urine, and anthropometric data were obtained from teenagers every 6 mo over an 18-mo period. Samples were collected once from adults. Data were analyzed by Student's t test and Fisher's protected least significant difference test for comparing smokers and non-smokers and for analyzing period effects in each group. RESULTS: Serum nicotine and cotinine concentrations were higher in smokers than in non-smokers. Blood pressures were higher in teenage (at 0 and 12 mo) and adult smokers than in non-smokers. Extracellular superoxide dismutase activities and concentrations of serum vitamin C and folate were lower in smokers in the teenage (at 0, 12, or 18 mo) and adult groups. Serum ceruloplasmin activities and thiobarbituric acid-reactive substance production were not influenced by smoking. In adults, serum copper concentrations were higher in smokers than in non-smokers. This parameter for teenagers did not change consistently throughout the study. CONCLUSIONS: Similar to adults, cigarette smoking by teenagers has a negative effect on oxidant defense systems.

Kosten T; Owens M. Immunotherapies for substance abuse. IN: Dewey WL, ed. Problems of Drug Dependence 2003: Proceedings of the 65th Annual Scientific Meeting. Rockville MD: National Institute on Drug Abuse, 2004. pp. 31-33. (0 refs.)

Medications based on immunological therapies are currently in pre-clinical and human trials for cocaine, nicotine, methamphetamine, and phencyclidine (PCP). The purpose of this symposium is to show experimental data from animal and human models of clinical scenarios in which these new therapeutic approaches might prove useful. These modes include reduction of drug self-administration, treatment of excessive drug use, and prevention of brain or cardiac toxicity. As an example, pre-clinical behavioral studies in rats show active immunization against cocaine and nicotine, or passive administration with anti-methamphetamine monoclonal antibodies might be used to reduce drug self-administrant, even when the drug dowse appears to exceed the apparent antibody binding capacity. Experimental data is show about the use methamphetamine and phencyclidine monoclonal antibodies for the treatment of excessive drug use. Data is also presented on the immunization of rats with a nicotine conjugate vaccine for the passive transfer of nicotine-specific antibodies substantially reduce maternal nicotine distribution to the fetal brain and attenuates the acquisition of nicotine self-administration. Finally, results from human outpatient clinical trials of a cocaine vaccine, along with their urine toxicology results. These data show that more frequent vaccinations of humans can lead to higher antibody levels. excellent reductions in cocaine use with minimal side effects.

Public Domain

Kovacs EJ; Faunce ED; Messingham KAN. Ethanol and burn injury: Estrogen modulation of immunity. Alcohol 33(3): 209-216, 2004. (121 refs.)

A good deal of clinical evidence supports the idea that ethanol exposure is a causative factor in the occurrence of burn or other traumatic injury. In addition, more recent evidence reveals that individuals who sustain injury while under the influence of ethanol suffer from increased morbidity and mortality compared with those with comparable injuries who did not consume ethanol. Many of the complications seen in ethanol-exposed, burn-injured subjects result from depressed immune responses, which render the host unable to fight off infectious organisms. Both injury and ethanol exposure independently affect cellular immune responses, including delayed-type hypersensitivity and splenocyte proliferative responses, and the combined insult of ethanol exposure and injury acts in conjunction to increase further the magnitude and duration of immunosuppression. It is interesting that these immune responses can be restored experimentally in male, but not in female, mice by administration of low, proestrous levels of estrogen. The complexity of the responses after injury in ethanol-exposed subjects is multiplied when the sex of the subjects is added to the equation. This is due, in part, to the effect of the combined insult of injury and ethanol on the production of gonadal steroid hormones in males and females and the direct effects of those hormones on cytokine gene expression in sensitive cell types such as the macrophage. Evidence seems to indicate that cellular immune responses after ethanol exposure and burn injury differ in kinetics and magnitude for male and female subjects, and, hence, the therapeutic interventions to treat burn-injured patients should take into account both sex and ethanol exposure.

Kovacs EJ; Jerrells TR. Alcohol and immunology: Introduction to and summary of the 2003 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 33(3): 171-174, 2004. (8 refs.)

The 8th Meeting of the Alcohol and Immunology Research Interest Group (AIRIG) was held at Loyola University Medical Center, Maywood, Illinois, USA, on November 21, 2003. Reports from multiple laboratories reveal that the functional integrity of the immune system is of paramount importance to the survival of the individual after infection or injury. Evidence supports the idea that exposure to alcohol causes dysregulation of both the innate and the adaptive arms of the immune system. Gaining a better understanding of how alcohol interferes with normal inflammatory and immunoregulatory processes will aid researchers in the design of therapeutic interventions that can be used to improve these responses to better fight infection and maintain the health of the individual. At this meeting, nine speakers presented a summary of their recent work on the combined effects of ethanol and injury, infection, or inflammatory challenge. Topics were (1) T-cell activation after chronic ethanol ingestion in mice, (2) effect of ethanol consumption on the severity of acute viral-mediated pancreatitis, (3) ethanol and alveolar macrophage dysfunction, (4) impaired intestinal immunity and barrier function: a cause for enhanced bacterial translocation in alcohol intoxication and burn injury, (5) immune consequences of the combined insult of acute ethanol exposure and burn injury, (6) consequences of alcohol-induced dysregulation of immediate hemodynamic and inflammatory responses to trauma/hemorrhage, (7) regulation of tumor necrosis factor-alpha production by Kupffer cells after chronic exposure to ethanol, (8) acute exposure to ethanol and suppression of cytokine responses induced through Toll-like receptors, and (9) inhibition of antigen-presenting cell functions by alcohol: implications for hepatitis C virus infection. We anticipate that the work presented at the 8th Meeting of AIRIG, summarized in this article, and presented in the nine articles to follow in this Special Issue of Alcohol will stimulate ideas that will develop into research projects in these topical areas.

Kraft B; Kress HG. Cannabinoids and the immune system. Of men, mice and cells. (review). Schmerz 18(3): 203-+, 2004. (40 refs.)

The medical use of cannabis or cannabinoid compounds is controversial. Cannabinoids like the Delta9-THC (tetrahydrocannabinol) or the synthetic derivative Nabilone are available against cancer- and HIV-associated cachexia, nausea and vomiting. Over the last 20 years, the cannabinoid receptors CB1 and CB2 and their endogenous ligands have been found. The involvement of this endogenous cannabinoid signalling system in feeding, appetite, pain perception and immunomodulation could be demonstrated using animal and in vitro studies. Thus,the concern about immunosuppressive effects in humans using medical cannabinoid preparations grew. However, up to now most human studies have failed to demonstrate a well-defined and reproducible immunosuppressive cannabinoid-effect. Only the smoking of marijuana showed a significant local immunosuppression of the bactericidal activity of human alveolar macrophages. In animal studies, cannabinoids were identified as potent modulators of cytokine production, causing a shift from Th1 to Th2 cytokines. In consequence, a compromised cellular immunity was observed in these animals, resulting in enhanced tumor growth and reduced immunity to viral infections. In vitro, immunosuppressive effects were shown in all immune cells, but only at high micromolar cannabinoid concentrations not reached under normal clinical conditions. In conclusion,there is no evidence that cannabinoids induce a serious, relevant immunosuppression in humans,with the exception of marijuana-smoking which may affect local brocho-alveolar immunity.

Laso FJ; Vaquero JM; Almeida J; Marcos M; Orfao A. Chronic alcohol consumption is associated with changes in the distribution, immunophenotype, and the inflammatory cytokine secretion profile of circulating dendritic cells. Alcoholism: Clinical and Experimental Research 31(5): 846-854, 2007. (47 refs.)

Background: Alcoholism is frequently associated with altered immune responses, limited information being available on its effects on dendritic cells (DC). In the present study we analyze the effects of chronic alcoholism on circulating DC. Methods: For the first time we studied the numerical distribution of DC in peripheral blood (PB), their immunophenotype, and their ex vivo pattern of spontaneous cytokine secretion, in chronic alcoholic patients without liver disease (AWLD group; n=17) and active ethanol (EtOH) intake, as well as in subjects with alcohol liver cirrhosis (ALC group; n=21). Results: A significantly decreased HLADR expression and an increased reactivity for CD123 was observed on PB DC from AWLD patients; additionally, increased secretion of interleukin (IL) 1 beta, IL6, IL12, and tumor necrosis factor-alpha (TNF alpha) by DC was also noted in this group. Conversely, patients with ALC and at least 1 year of alcohol withdrawal (ALCAW group) showed a decreased number of total circulating DC, whereas ALC patients with active EtOH intake (ALCET group) had an abnormally low production of IL1 beta and TNF alpha by PB DC. Conclusion: Chronic alcoholism in the absence of liver disease is associated with an increased secretion of inflammatory cytokines by PB DC, whereas ALCAW and ALCET patients show decreased numbers of circulating DC and reduced secretion of these cytokines, respectively.

Ma Y; Meregalli M; Hodges S; Davies N; Bogdanos DP; Fargion S. Alcohol dehydrogenase: An autoantibody target in patients with alcoholic liver disease. International Journal of Immunopathology and Pharmacology 18(1): 173-182, 2005. (32 refs.)

The link between alcohol consumption and liver disease is not direct and several factors including autoimmunity to hepatocyte components have been implicated. We have previously identified alcohol dehydrogenase (ADH) as an autoantigen in autoimmune liver disease and in a proportion of patients with alcoholic liver disease. The aim of the present study is to investigate the association between the presence of anti-ADH antibodies, alcohol consumption and severity of liver damage in alcoholic patients. The presence of antibodies to human ADH beta2 and horse ADH was investigated in 108 patients with documented history of alcohol consumption and alcohol related liver disease, 86 being active alcohol abusers and 22 on sustained alcohol withdrawal, 39 with non-alcohol related disease and 22 normal subjects. Antibodies to either ADH form were more frequently detected in active alcohol abusers (55/86, 64%) than in patients on sustained alcohol withdrawal longer than 6 months (1/8, 13%, P<0.005), HBV infection (2/8, 25%, P=0.03), non-alcohol related disease (9/29, 23%, P<0.0001) and in normal controls (3/22, 14%, P<0.0001); were more frequent in patients with cirrhosis than in those with steatosis (26/34, 76% vs 34/64, 53%, P=0.02); and were associated with elevated levels of ALT (anti-ADH beta2, P<0.05), immunoglobulin A (P<0.05) and gamma-glutamyl transpeptidase (P=0.01). Anti-ADH antibody positive serum samples were able to inhibit the enzymatic activity of ADH. These findings suggest that anti-ADH antibodies may be triggered by alcohol consumption and act as a disease activity marker in alcoholic liver disease.

Manfredsdottir VF; Vikingsdottir T; Jonsson T; Geirsson AJ; Kjartansson O; Heimisdottir M et al. The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology 45(6): 734-740, 2006. (36 refs.)

Objective. To study the effect of tobacco smoking and rheumatoid factor (RF) isotypes on disease activity and joint damage in early rheumatoid arthritis (RA). Methods. One hundred early RA patients were followed prospectively for 2 yr. They were evaluated at recruitment and at 6 and 24 months. Sociodemographic information included smoking history, and radiographs of hands and feet were obtained. RF was monitored by IgM- and IgA-specific RF enzyme-linked inummosorbent assay and by agglutination, and serial measurements were also obtained for C-reactive protein. The influence of tobacco smoking and RF positivity on disease outcome was evaluated using multivariate analysis. Covariates for the regression analysis included sex, age, coffee consumption and IgA-RF positivity. Results. A gradient of increase in disease activity was observed from never smokers to former smokers to current smokers during the 2 yr of observation, defined by number of swollen joints (SJC), tender joints (TJC) and visual analogue scale for pain (P < 0.001, P = 0.02 and P = 0.005, respectively), but smoking status did not influence radiological progression. Ever smokers were more often IgA RF positive (P < 0.05). IgA RF-positive patients had more active disease (SJC P = 0.002, TJC P = 0.01) and showed more radiological progression (P < 0.0001) compared with IgA RF-negative patients. Of the RF-positive patients 22% had elevated IgM RF without IgA RF and these patients showed similar disease activity and radiological joint progression to the RF-negative patients. None of these associations were explained by possible confounders. Conclusion. Tobacco smoking has an adverse effect on patients with early RA and this is possibly immunologically mediated. IgM RF does not predict poorer prognosis in RA unless it is associated with a concomitant elevation of IgA RF.

Massi P; Vaccani A; Parolaro D. Cannabinoids, immune system and cytokine network. (review). Current Pharmaceutical Design 12(24): 3135-3146, 2006. (102 refs.)

How cannabinoids influence immune function has been examined extensively in the last 30 years. Studies on drug-abusing humans and animals, as well as in vitro models employing immune cell cultures, have shown that marijuana, natural and endogenous cannabinoid compounds are immunomodulators. These substances modulate host resistance to bacterial, protozoan and viral infections as well as they can profoundly affect the Th1/Th2 response. Recently, two types of cannabinoid receptor, CB1 and CB2, have been discovered. While CBI is expressed primarily in the brain, CB2 is peculiar of the immune cells. Cannabinoid receptors have been shown to be involved in some but not all of immune effects. Nevertheless, their identification provides a specific mechanism of action in the attempting to find out how exogenous cannabinoids and endogenous cannabinoid system affect the immune apparatus, strengthen the hypothesis of cannabinoids as immunomodulators. As support to this theory, enough evidence exists to suggest that the cannabinoid system significantly affects almost every component of the immune response machinery and impacts the functioning also of the cytokine network. The evaluation of the biological consequences of these drug-induced cytokine changes has also dramatically become important considering not only the impact of cytokines on immune system per se but also envisaging their influence in cancer, inflammation, autoimmune disease, brain injury, hematopoictic colony formation in which cannabinoids have demonstrated a clear role as important modulators.

Miller GE; Cohen S; Pressman S; Barkin A; Rabin BS; Treanor JJ. Psychological stress and antibody response to influenza vaccination: When is the critical period for stress, and how does it get inside the body? Psychosomatic Medicine 66(2): 215-223, 2004. (41 refs.)

Objectives: This study attempted to determine whether stress of moderate intensity could modulate the antibody response to an influenza vaccination in healthy young adults, identify critical periods during which stress could influence antibody response, and delineate behavioral and biological pathways that might explain relations between stress and antibody. Methods: A cohort of 83 healthy young adults underwent 13 days of ambulatory monitoring before, during, and after vaccination. Four times daily, subjects reported the extent to which they felt stressed and overwhelmed and collected a saliva sample that was later used to measure cortisol. A battery of health practices (cigarette smoking, alcohol use, physical activity, sleep hygiene) was assessed daily. Antibody titers to the vaccine components were measured at baseline and at 1-month and 4-month follow-up assessments. Results and Conclusions: To the extent that they reported higher levels of stress across the monitoring period, subjects exhibited poorer antibody responses to the New Caledonia strain of the vaccine. Stress ratings on the 2 days before the vaccine and the day it was given were not associated with antibody response. However, the 10 days afterward appeared to be a window of opportunity during which stress could shape the long-term antibody response to varying degrees. With respect to potential mediating pathways, little evidence emerged in favor of cortisol secretion, alcohol consumption, physical activity, or cigarette smoking. However, analyses were consistent with a pattern in which feelings of stress and loss of sleep become locked into a feed-forward circuit that ultimately diminishes the humoral immune response. These findings may shed light on the mechanisms through which stress increase vulnerability to infectious disease.

Misery L. Nicotine effects on skin: Are they positive or negative? (review). Experimental Dermatology 13(11): 665-670, 2004. (69 refs.)

The adverse effects of tobacco on the skin are well known but the role of nicotine is more controversial. Nicotinic receptors are expressed in the skin, on keratinocytes, fibroblasts and blood vessels. Nicotine induces vasoconstriction associated with local hyperaemia. It inhibits inflammation through effects on central and peripheral nervous system and through direct effect on immune cells. It delays wound healing and accelerates skin aging. The role of nicotine on skin diseases remains unclear. Therapeutic effects of nicotine could be possible and this a new stimulating field of research.

Molina PE; Zambell KL; Norenberg K; Eason J; Phelan H; Zhang P et al. Consequences of alcohol-induced early dysregulation of responses to trauma/hemorrhage. Alcohol 33(3): 217-227, 2004. (75 refs.)

Acute alcohol intoxication is a frequent underlying condition associated with traumatic injury. Studies from our laboratory have been designed to examine the early hemodynamic, proinflammatory, and neuroendocrine alterations in responses to hemorrhagic shock in surgically catheterized, conscious, unrestrained, male Sprague-Dawley rats during acute alcohol intoxication (1.75-g/kg bolus, followed by a constant 15-h infusion at a rate of 250-300 mg/kg/h). With both fixed-pressure (40 mm Hg) and fixed-volume (50%) hemorrhagic shock, followed by fluid resuscitation with Ringer's lactate, acute (15 h) alcohol intoxication has been shown to impair significantly the immediate hemodynamic, metabolic, and inflammatory counterregulatory responses to hemorrhagic shock. Alcohol intoxication enhanced hemodynamic instability during blood loss and impaired the recovery of mean arterial blood pressure during fluid resuscitation. Activation of neuroendocrine pathways involved in restoring hemodynamic stability was significantly attenuated in alcohol-intoxicated hemorrhaged animals. The hemodynamic and neuroendocrine impairment is associated with enhanced expression of lung and spleen tumor necrosis factor, and it suppressed circulating neutrophil function. In addition, neuroimmune regulation of cytokine production by spleen-derived macrophages obtained from alcohol-intoxicated hemorrhaged animals was impaired when examined in vitro. We hypothesize that impaired neuroendocrine activation contributes to hemodynamic instability, which, in turn, prolongs tissue hypoperfusion and enhances risk for tissue injury. Specifically, the early dysregulation in counterregulatory responses is hypothesized to affect host defense mechanisms during the recovery period. We examined host response to systemic (cecal ligation and puncture) and localized (pneumonia) infectious challenge in animals recovering from hemorrhage during acute alcohol intoxication. Increased morbidity and mortality from infection were observed in alcohol-intoxicated hemorrhaged animals. Our results indicate that alcohol-induced alterations in early hemodynamic and neuroimmune responses to shock have an impact on susceptibility to an infectious challenge during the early recovery period.

Moran A; Harbour DV; Teeter LD; Musser JM; Graviss EA. Is alcohol use associated with cavitary disease in tuberculosis? Alcoholism: Clinical and Experimental Research 31(1): 33-38, 2007. (30 refs.)

Background: Alcohol mediates detrimental alterations in the immune response to Mycobacterium tuberculosis. The association between quantity and frequency of alcohol use and the prevalence of cavitary disease in tuberculosis (TB) has not been analyzed. To investigate the relationship of alcohol use and the prevalence of cavitary disease in a 6-year population-based data set of individuals with TB. Methods: We assessed quantity and frequency of alcohol use (daily alcohol use, years of alcohol use, and lifetime alcohol use) with a standardized questionnaire. The study group consisted of 1,250 patients analyzed for cavitary disease (HIV sero-negative subjects that were 18 years or older). Significant covariates for cavitary disease were entered into multiple logistic regression models. Results: Although daily alcohol use, years of alcohol use, and alcohol use 30 days or 6 months before symptom onset were significant predictors of cavitary disease in univariate analysis, no independent associations were found between alcohol use and cavitary disease in the multivariate analysis. Only diabetes mellitus was independently associated with cavitary disease at any level or frequency of alcohol use. Conclusion: Alcohol use is not independently associated with increased prevalence of cavitary disease in adult patients with TB.

Motivala SJ; Dang J; Obradovic T; Meadows GG; Butch AW; Irwin MR. Leptin and cellular and innate immunity in abstinent alcoholics and controls. Alcoholism: Clinical and Experimental Research 27(11): 1819-1824, 2003. (38 refs.)

Background: Basic studies indicate that in vitro and in vivo doses of leptin modulate cellular immune responses. Given evidence that concentrations of leptin are altered in alcoholics who also show immune abnormalities, this study examined the relationships between circulating levels of leptin and markers of cellular and innate immunity. Methods: Circulating levels of leptin, natural killer cell (NK) activity, interleukin-2 (IL-2)-stimulated NK activity, and concanavalin A-stimulated production of IL-2, IL-6, IL-10, and IL-12 were compared between abstinent DSM-IV alcohol-dependent men (n = 27) and age- and gender-matched controls (n 34). Results: As compared with controls, alcoholics showed lower NK activity (p < 0.01) and a trend for lower levels of leptin (p = 0.055). In the total sample, leptin predicted NK activity (β = 0.33; p < 0.05) after controlling for the confounding influence of body mass index, alcohol intake, and smoking. Leptin was not correlated with any of the cytokine measures. To examine whether the effects of leptin were mediated by its direct action on NK, additional studies examined in vitro effects of leptin on NK activity in healthy volunteers (n = 10); leptin doses (0.1, 1, and 10 nM) yielded levels of NK activity comparable to those with media alone. Conclusions: These data show that circulating levels of leptin are associated with NK activity in humans and suggest that abnormal in vivo concentrations of leptin may contribute to the declines of NK activity in alcoholics who are at risk for infectious diseases.

Nagy LE. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. (review). Experimental Biology and Medicine 228(8): 882-890, 2003. (102 refs.)

The innate immune system is responsible for the rapid, initial response of the organism to potentially dangerous stresses, including pathogens, tissue injury, and malignancy. Pattern-recognition receptors of the toll-like receptor (TLR) family expressed by macrophages provide a first line of defense against microbial invasion. Activation of these receptors results in a stimulus-specific expression of genes required to control the infection, including the production of inflammatory cytokines and chemokines, followed by the recruitment of neutrophils to the site of infection. The early stages in the development of alcoholic liver disease (ALD) follow a pattern characteristic of an innate immune response. Kupffer cells, the resident macrophages in the liver, are activated in response to bacterial endotoxins (lipopolysaccharide, LPS), leading to the production of inflammatory and fibrogenic cytokines, reactive oxygen species, as well as the recruitment of neutrophils to the liver. One mechanism by which chronic ethanol can turn the highly regulated innate immune response into a pathway of disease is by disrupting the signal transduction cascades mediating the innate immune response. Recent studies have identified specific modules in the TLR-4 signaling cascade that are disrupted after chronic ethanol exposure, including CD14 and the mitogenactivated protein kinase family members, ERK1/2 and p38. Enhanced activation of these TLR-4 dependent signaling pathways after chronic ethanol likely contributes to the development of alcoholic liver disease.

Nakata A; Takahashi M; Irie M; Fujioka Y; Haratani T; Araki S. Relationship between cumulative effects of smoking and memory CD4+T lymphocyte subpopulations. Addictive Behaviors 32(7): 1526-1531, 2007. (11 refs.)

Previous studies have found that smoking is a strong factor that increases peripheral blood CD4+ T lymphocytes. However, most studies did not assess the cumulative long-life exposure of smoking on differential lymphocyte populations. In this study, to clarify the association of smoking habits and circulating lymphocytes, we conducted a cross-sectional study of 60 male current smokers. Smoking status was estimated by number of cigarettes smoked per day, smoking years, and Brinkman Index (BI) as calculated by multiplying the number of cigarettes smoked per day by the smoking years. Counts of CD4+CD45RO+CD69+ T and CD4+CD45RO+ T lymphocytes were strongly and positively correlated with BI and remained highly significant after controlling for alcohol drinking, leisure-time physical activity, and caffeine intake (r(p)>.465, p<.001). These lymphocytes were also significantly correlated with the number of cigarettes smoked per day and smoking years, but the association was weaker than the BI. The findings suggest that the CD4+CD45RO+CD69+ T and CD4+CD45RO+ T lymphocytes are sensitive to cumulative effect of smoking, and may serve as a potential immuno-biomarker for active smoking.

Neri S; Bruno CM; Pulvirenti D; Malaguarnera M; Italiano C; Mauceri B et al. Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers. Psychopharmacology 179(3): 700-704, 2005. (18 refs.)

Rationale: Buprenorphine may be a useful alternative option to methadone in addicts. Opioids can produce severe changes in the immune system. Objectives: The objectives of this study are to compare the effect of sublingual buprenorphine and methadone on the immune system and to compare the two substances on the drying-out program compliance. Methods: We studied 62 randomized outpatients for a period of 12 months. Subjects (55 males and 7 females; mean age 25 +/- 4 years; average history of heroin abuse being 2 years) on maintenance treatment were assigned in two groups (A and B). Methadone chloride (medium dose 100 mg/day) was administered to group A, whereas group B received sublingual buprenorphine (32.40 +/- 2.8 mg/day). Urine toxicological screening, plasma levels of TNF-alpha interleukin-1, interleukin-beta, lymphocyte CD14 and a self-rating depression questionnaire were measured. Results: Urine screening was negative for opiates in 17.6% of group A and in 10.7% of group B (p< 0.001; r= 0.62). Depression score was 62 +/- 2 in group A and 55 +/- 3 in group B (p< 0.01). Cytokine and CD14 revealed higher concentrations both in groups A and B without significant differences (p> 0.05) between the two groups. Conclusions: The effects of buprenorphine and methadone tested on the immune system were overlapping in our patients. The elevated cytokine levels observed may suggest that the two drugs stimulate immunologic hyperactivation of an immune system that was formerly inhibited by heroin. Furthermore, our data suggest that buprenorphine can be a valid alternative to methadone in maintenance treatment of chronic heroin abuse and referred a marked decline in depression.

Nouri-Shirazi M; Guinet E. A possible mechanism linking cigarette smoke to higher incidence of respiratory infection and asthma. Immunology Letters 103(2): 167-176, 2006. (48 refs.)

T helper type 1 (Th1) cells are responsible for cell-mediated immunity against invading pathogens, while Th2 cells provide help to B cells and control allergic responses. The polarization of naive Th cells into Th1 or Th2 subsets is controlled by dendritic cells (DCs) migrating from the periphery to draining lymph nodes. Migrating DCs carry not only antigen-specific 'signal I' and costimulatory 'signal 2', but also Th-polarizing,signal 3' that reflects the nature of the pathogen and the character of the infected tissue. Any changes imposed by external factors on the DC lifecycle may result in an inappropriate immune response. Here we show that DCs developed in a nicotinic environment (nicDCs) fail to support the terminal development of effector memory Th1 cells due to their differential expression of costimulatory molecules and lack of IL-12 production. Interestingly, they adopt critical Th1-promoting function necessary to prevent and fight infections only when the total balance of environmental signals strongly favors Th1 immunity. Notably, in a Th2-biased environment, nicDCs provoke stronger than normal Th2 responses which predisposes the development and exacerbation of asthma. These results help explain the two opposing effects of cigarette smoke on respiratory immune defense mechanisms: (a) immunosuppression against infectious agents and (b) exacerbation of asthma.

Nutt D; Lingford-Hughes A. Infecting the brain to stop addiction? (editorial). Proceedings of the National Academy of Sciences 101(31): 11193-11194, 2004. (7 refs.)

Drug abuse is a major public health problem, and, although there are many treatments of proven efficacy, the majority of patients are not permanently cured, with relapse rates on the order of 70% or more in the first years for the treatment of almost all drugs of addiction. Therefore, there is a great need for new and improved therapies. Carrera et al. have pioneered the use of one of the oldest proven medical interventions, immunization, in the treatment of cocaine dependence. Their initial studies revealed that it is possible to vaccinate animals against cocaine by using either a blocking antibody or catalytic antibody approach. The blocking antibody binds cocaine and therefore extracts it from the blood; this seems to be the more promising method, because the current catalytic antibodies only minimally accelerate the clearance of cocaine. However, the blocking antibody technique provides only a peripheral blockade, and so any cocaine that is not "mopped up" by antibodies in plasma can enter the brain and give the reinforcing actions that perpetuate the cycle of addiction and dependence. The work by Carrera et al. in a recent issue of PNAS moves the field by utilizing a concept originated for the treatment of Alzheimer's disease in which an antibody to -amyloid was delivered to the brain in a (bacterio)phage vector. Here, the animal is infected with a phage that targets the brain and that has been engineered to express thousands of copies of the cocaine-binding antibody. It reproduces in the brain, thereby generating large amounts of blocking antibody. When cocaine enters the brain, some of it binds to the antibody and, therefore, is not available to perform its usual action: to increase dopamine, the neurotransmitter that is thought to mediate its actions. To maximize access of phage to the brain and minimize peripheral infection, the phage vaccine was administered intranasally, where it is presumed to enter the olfactory nerve endings and move down the axons into the brain. Antagonist therapies are not appealing as because they are not reinforcing. Perhaps an alternative strategy would be to produce an enduring blockade before first exposure as a preventative measure, such as is done with vaccination against measles and other infectious diseases. This would, of course, be ethically controversial, although given the fact that cocaine dependence is more damaging to many individuals than measles, it is an option that should be debated.

Pacifici R; Zuccaro P; Farre M; Poudevida S; Abanades S; Pichini S et al. Combined immunomodulating properties of 3,4-methylenedioxymethamphetamine (MDMA) and cannabis in humans. Addiction 102(6): 931-936, 2007. (12 refs.)

Aims Cell-mediated immune function and the occurrence of mild infectious diseases was investigated. Participants Polydrug consumers of 3,4-methylenedioxymethamphetamine (MDMA) and cannabis (n = 37) compared to cannabis users only (n = 23) and control group (n = 34). Design A longitudinal prospective study with three cross-sectional evaluations at time 0 and at 6 months and 1 year was performed. Findings At baseline, a significant decrease in interleukin (IL)-2 and an increase in anti-inflammatory transforming growth factor (TGF)-beta 1, together with a decrease in the number of total lymphocytes, CD4 and natural killer (NK) cells were observed in the MDMA-cannabis group, with intermediate alterations in the cannabis group. Immune alterations observed at baseline were sustained over time. No differences were found between regular and occasional MDMA users. A significantly higher rate of mild infections in regular MDMA-cannabis users compared with occasional MDMA-cannabis users and the remaining groups was observed. Conclusions The present data confirm that long-term alterations in immunological homeostasis may result in general health status impairment and subsequent increased susceptibility to infection and immune-related disorders.

Pavia CS; La Mothe M; Kavanagh M. Influence of alcohol on antimicrobial immunity. Biomedicine & Pharmacotherapy 58(2): 84-89, 2004. (60 refs.)

Prolonged consumption of excessive amounts of alcohol by itself, as well as possibly leading to a state of alcoholism, has been a long-standing biological/social problem. As a major public health concern, there is an estimated expenditure of about 20% of total health care costs for medical/hospital care related to alcohol-induced illness. In addition, a significant proportion of both men and women who are hospitalized can be classified as alcoholics. This review focuses primarily on one of the many biomedical problems attributed to alcohol abuse-its adverse effects on our immune-defense system. A considerable body of evidence has mounted, over the past several decades, indicating that those who abuse alcohol are more susceptible to certain infectious disorders and are more prone to bacteremia. Such infections tend to be continuous and are often associated with a high rate of mortality. Also, along these lines, various and suitable animal models have been developed to further elucidate what the causes are for the greater frequency and severity of infectious illnesses, and this review deals primarily with those studies linking alcohol abuse to disruption in the normal functioning of the host's immune surveillance system. Based on the results from both clinical and experimental studies, it would seem that exposure to high levels of alcohol causes decreased humoral and cellular immune responses, thereby seriously limiting our ability to be protected from certain infectious agents.

Peterson E; Owens SM; Henry RL. Monoclonal antibody form and function: manufacturing the right antibodies for treating drug abuse. AAPS Journal 8(2): e383-390, 2006. (32 refs.)

Drug abuse continues to be a major national and worldwide problem, and effective treatment strategies are badly needed. Antibodies are promising therapies for the treatment of medical problems caused by drug abuse, with several candidates in preclinical and early clinical trials. Monoclonal antibodies can be designed that have customized affinity and specificity against drugs of abuse, and because antibodies can be designed in various forms, in vivo pharmacokinetic characteristics can be tailored to suit specific clinical applications (eg, long-acting for relapse prevention, or short-acting for overdose). Passive immunization with antibodies against drugs of abuse has several advantages over active immunization, but because large doses of monoclonal antibodies may be needed for each patient, efficient antibody production technology is essential. In this minireview we discuss some of the antibody forms that may be effective clinical treatments for drug abuse, as well as several current and emerging production systems that could bridge the gap from discovery to patient use.

Pruett BS; Pruett SB. An explanation for the paradoxical induction and suppression of an acute phase response by ethanol. Alcohol 39(2): 105-110, 2006. (31 refs.)

Binge ethanol (EtOH) consumption suppresses inflammatory responses and resistance to infection, but paradoxically it is associated with increased levels of acute phase proteins (which are indicators of inflammation) and an increased risk of inflammation-mediated pathologies such as cardiovascular disease and cirrhosis of the liver. The latter effect may be mediated by increased translocation of bacteria leading to activation of toll-like receptor 4 (TLR4). In this study, the dose-response and time course of the effects of EtOH alone or EtOH in conjunction with a TLR4 agonist (lipopolysaccharide [LPS]) were evaluated in mice. EtOH alone at a dosage of 6 g/kg induced an acute phase response (as indicated by enzyme-linked immunosorbent assay for serum amyloid A and serum amyloid P) that was maximal 24 h after dosing. Lower dosages of EtOH did not have this effect but did suppress the acute phase response to LPS and the production of interleukin-6 up to 3 h after dosing. EtOH at 6 g/kg did not induce an acute phase response in C3H/HeJ (TLR4 mutant) mice, indicating that this response is mediated through TLR4. These results provide a resolution for the apparently paradoxical pro- and anti-inflammatory actions of EtOH with regard to acute phase responses.

Pruett SB; Zheng Q; Fan R; Matthews K; Schwab C. Acute exposure to ethanol affects Toll-like receptor signaling and subsequent responses: An overview of recent studies. Alcohol 33(3): 235-239, 2004. (28 refs.)

Ethanol suppresses innate resistance to a variety of microbes, and findings of studies from both our laboratory and other laboratories indicate suppression of responses is mediated through two Toll-like receptors (TLRs): TLR3 and TLR4. In this article, we review recent findings from studies in our laboratory, indicating that ethanol also suppresses responses mediated through other TLRs. Considering the importance of TLR-mediated responses in innate immunity, this supports the possibility that suppression of these responses may constitute a major mechanism by which ethanol suppresses innate immunity. In addition, ethanol-induced changes in cellular signaling and in patterns of gene expression induced through TLR3 were examined in mouse peritoneal macrophages, and these results are reviewed in this article. Signaling through TLR3 was inhibited, and results of DNA microarray analysis supported the notion that inhibition of an interferon-related amplification loop might be responsible for suppression of gene expression for several effector molecules of innate immunity and inflammation not previously known to be altered by ethanol. Thus, ethanol alters responses through most or all mouse TLRs, and this suppresses expression of a wide range of innate immune mediators.

Redwine L; Dang J; Hall M; Irwin M. Disordered sleep, nocturnal cytokines, and immunity in alcoholics. Psychosomatic Medicine 65(1): 75-85, 2003. (58 refs.)

The authors examine the relationships between sleep, nocturnal expression of immunoregulatory cytokines, and natural killer (NK) cell activity in alcoholic patients as compared with control subjects. 24 alcoholic patients and 23 comparison control subjects underwent all-night polysomnography and serial blood sampling at 23:00, 03:00, and 06:30 hrs. Stimulated expression of TH1 (interferon gamma, IFN-gamma), anti-inflammatory/TH2 (interleukin 10, IL-10), and proinflammatory cytokines (IL-6) was measured along with NK cell activity across the night. Alcoholic patients showed lower levels of IL-6 production, suppression of the IL-6/IL-10 ratio, and a reduction of NK cell activity, coupled with losses of delta sleep and increases of rapid eye movement sleep, as compared with control subjects. In addition, alcoholics showed a persistent low ratio of IFN-gamma/IL-10 and reduced levels of NK cell activity, whereas controls had increases of these 2 immune measures across the night. IL-6 also differentially changed in the 2 groups; alcoholics showed increases and controls had decreases of IL-6 from 03:00 hrs to 06:30 hrs. At 06:30 hrs, rapid eye movement sleep predicted increases of IL-6 and decreases of NK cell activity independent of the relative contribution of age and chronic alcohol consumption.

Romeo J; Warnberg J; Nova E; Diaz LE; Gomez-Martinez S; Marcos A. Moderate alcohol consumption and the immune system: A review. British Journal of Nutrition 98(Supplement 1): S111-S115, 2007. (46 refs.)

Increasing evidence suggests that light to moderate amounts of polyphenol-rich alcoholic beverages like wine or beer could have health benefits. Scientists have long debated the effects of alcohol on immune function, showing on the one hand, that high doses of alcohol consumption can directly suppress a wide range of immune responses, and that alcohol abuse is associated with an increased incidence of a number of infectious diseases. On the other hand, moderate alcohol consumption seems to have a beneficial impact on the immune system compared to alcohol abuse or abstinence. Therefore, the link between alcohol consumption, immune response, as well as infectious and inflammatory processes remains not completely understood. With this in mind, it is important to realise that other factors, unrelated or indirectly related to immune function, like drinking patterns, beverage type, amount of alcohol, or gender differences, will affect the influence that alcohol consumption may have on the immune system. This review summarises published data describing the effects that light to moderate amounts of polyphenol-rich beverages like wine or beer seem to have on immunity in healthy adults.

Roth MD; Whittaker K; Salehi K; Tashkin DP; Baldwin GC. Mechanisms for impaired effector function in alveolar macrophages from marijuana and cocaine smokers. Journal of Neuroimmunology 147(1-2): 82-86, 2004. (49 refs.)

Lung macrophages provide a first line of host defense against inhaled pathogens and their function is impaired in the lungs of inhaled substance abusers. In order to investigate the mechanism for this impairment, alveolar macrophages (AM) were recovered from nonsmokers (NS), regular tobacco smokers (TS), marijuana smokers (MS), or crack cocaine smokers (CS), and evaluated for their production of nitric oxide (NO) and the role of NO as an antimicrobial effector molecule. AM from NS and TS efficiently killed Staphylococcus aureus and their antibacterial activity correlated closely with the production of nitrite and the expression of mRNA encoding for inducible nitric oxide synthase (iNOS). In contrast, AM collected from MS and CS exhibited limited antimicrobial activity that was not affected by an inhibitor of iNOS, or associated with expression of iNOS. Treatment with either granulocyte/macrophage colony-stimulating factor (GM-CSF) or interferon-gamma restored the ability of these cells to produce NO and to kill bacteria. These findings confirm a significant role for NO as an antibacterial effector molecule used by normal human AM and suggest that this host defense mechanism is suppressed by habitual exposure to inhaled marijuana or crack cocaine in vivo.

Sacerdote P. Opioids and the immune system. Palliative Medicine 20(Supplement 1): S9-S15, 2006. (27 refs.)

Opioid compounds such as morphine produce powerful analgesia that is effective in treating various types of pain. In addition to their therapeutic efficacy, opioids can produce several well known adverse events, and, as has recently been recognized, can interfere with the immune response. The immunomodulatory activities of morphine have been characterized in animal and human studies. Morphine can decrease the effectiveness of several functions of both natural and adaptive immunity, and significantly reduces cellular immunity. Indeed, in animal studies morphine is consistently associated with increased morbidity and mortality due to infection and worsening of cancer. However, from several animal studies it emerges that not all opioids induce the same immunosuppressive effects, and evaluating each opioid's profile is important for appropriate analgesic selection. Buprenorphine is a potent opioid that is frequently prescribed for chronic pain. Acute intracerebroventricular administration of buprenorphine has been shown in rats not to affect cellular immune responses, while a statistically significant inhibition of the immune response was observed with morphine. In mouse studies, chronic administration of buprenorphine led to immune parameters important for antimicrobial responses or for anti-tumour surveillance (lymphoproliferation, natural killer (NK)-lymphocyte activity, cytokine production, lymphocyte number) being unaffected. In contrast, levels of these immune markers were significantly reduced when the potent mu-agonist fentanyl was administered, but recovered after longer periods as tolerance developed. Because the intrinsic immunosuppressive activity varies between individual opioids, predicting the outcome on immunity can be difficult. To study this, the effects of morphine, fentanyl and buprenorphine on NK-lymphocyte activity depressed by experimental surgery were examined in rats. Treating animals immediately after surgery with equianalgesic doses of morphine and buprenorphine significantly reduced surgery-induced immunosuppression. However, buprenorphine reverted NK-lymphocyte activity to preoperative levels, while in morphine-treated rats NK-lymphocyte activity was ameliorated, although not completely. In contrast, fentanyl did not prevent immunosuppression induced by surgery. Overall, from several animal studies it emerges that buprenorphine has the more favourable profile, being a potent analgesic devoid of intrinsic immunosuppressive activity.

Schleifer SJ; Keller SE; Czaja S. Major depression and immunity in alcohol-dependent persons. Brain, Behavior, and Immunity 20(1): 80-91, 2006. (61 refs.)

Altered immunity has been associated with both alcoholism and major depression (MD). We investigated the contribution of MD, as well as alcoholism, to in vitro measures of immunity in inner-city alcohol-dependent (SCID-DSM-III-R) persons and community nonabusers, all otherwise in good health. Methods. Alcohol-dependent persons at an ambulatory alcohol treatment center who did not abuse other substances were studied along with the comparison sample (total n=122). Enumerative and functional immune measures included leukocyte and lymphocyte subsets, mitogen response, natural killer cell activity (NKCA), and granulocytic phagocytosis. Results. Controlling for alcohol dependence, age, gender, racial background, and medical status, major depression was associated with decreased phytohemagglutinin (PHA) responses (p<.03), possibly decreased NKCA (p<.08), and increased circulating monocytes (p<.04). Controlling for major depression, age, gender, racial background, and medical status, alcohol dependence was associated with decreased circulating B lymphocytes (p<.02), possibly decreased CD56(+) (NK) cells (p<.06), and increased monocytes (p<.04). Responses to concanavalin A and pokeweed mitogen, granulocyte functions, and the composition of other leukocyte and lymphocyte subsets showed no evidence of being associated with major depression or with alcoholism (p>.1). Secondary analyses exploring factors such as recent alcohol use, cigarette use, and nutrition suggested that these factors accounted for the altered lymphocyte subsets associated with alcoholism and the possibly decreased NKCA with major depression. They did not account for the association of major depression with increased monocytes and decreased PHA. Discussion. major depression-associated immune changes in alcoholics are modest and consistent with those seen in major depression without alcoholism. Some major depression- and many alcoholism-associated immune effects appear related to factors such as cigarette use and recent alcohol exposure.

Schmid JMP; Kuehni CE; Strippoli MPF; Roiha HL; Pavlovic R; Latzin P; Swiss Pediatric Respiratory Research Group. Maternal tobacco smoking and decreased leukocytes, including dendritic cells, in neonates. Pediatric Research 61(4): 462-466, 2007. (22 refs.)

Maternal smoking in pregnancy is associated with respiratory diseases in the offspring, possibly due to prenatal influences on the developing immune system. We investigated whether maternal smoking in pregnancy was associated with cord blood leukocyte numbers, including precursor dendritic cells, adjusting for concomitant factors. In a prospective healthy birth cohort study, total leukocyte counts were reduced in neonates of smoking mothers [10.7 (8.4-13.0), n = 14] compared with nonexposed infants [14.7 (13.7-15.7), n = 74, p = 0.002] [geometric mean cells X 10(3)/mu L (95% confidence interval)]. All leukocyte subsets were decreased, most prominently segmented neutrophils [4.3 (2.8-5.7) versus 6.2 (5.5-6.8), p = 0.021], lymphocytes [3.8 (2.9-4.8) versus 5.0 (4.5-5.6), p = 0.036], and myeloid precursor dendritic cells [12.7 cells/mu L (9.1-17.8) versus 18.3 (15.8-21.2), p = 0.055]. These differences persisted after adjustment for possible confounders. Predictors of myeloid precursor dendritic cell numbers in multivariable models were maternal smoking (-5.1 cells/mu L, p = 0.042), age (-0.5 cells/mu L/y, p = 0.035), and, marginally, asthma (+8.1 cells/mu L, p = 0.075). The decrease of all leukocytes in neonates of smoking mothers could be clinically significant and suggests a decreased cell production, increased peripheral recruitment, or retention in bone marrow. Given the importance of dendritic cells in early immune responses, their decrease might reflect an impact of maternal smoking on the developing fetal immune system.

Sergio N; Salvatore T; Gaetano B; Davide P; Claudio I; Massimo L et al. Immune response in addicts with chronic hepatitis C treated with interferon and ribavirine. Journal of Gastroenterology and Hepatology 22(1): 74-79, 2007. (48 refs.)

The role played by the immune system in the progre