Addictive drugs and their relationship with infectious diseases

Authors


  • Editor: Willem van Leeuwen

Correspondence: Herman Friedman, Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, MDC Box 10, 12901 Bruce B. Downs Blvd, Tampa, FL 33612-4799, USA. Tel.: +1 813 974 2992; Fax: +1 813 974 4151; e-mail: hfriedma@hsc.usf.edu

Abstract

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.

Introduction

There has been an explosive accumulation of knowledge concerning the nature and mechanism of the immune response, including host immunity and resistance to bacterial infection as well as to infection by viruses, fungi and parasites. It is now recognized that both innate and adaptive immune responses are involved in recognition and interaction with microorganisms. The immune system is a complex network of cells and cytokines with the primary function of preventing infection. As well-controlled and resilient as the immune system is, however, many reports document the negative effects on immunity of environmental factors, including drugs of abuse (Reichman et al., 1979; Friedman et al., 1994, 1996, 2001, 2003, 2005; Almirall et al., 1999; Ruiz et al., 1999).

The immune system consists of a complex network of cells, including lymphocytes and monocytes (Fig. 1). Lymphocytes such as B cells are the primary cells involved in adaptive immunity. B cells are involved in producing specific immunoglobulin and antibodies. T cells are involved in producing cytokines and chemokines, which regulate many of the immune reactivities of the immune system. Phagocytic cells are also immunocytes, and include macrophages and dendritic cells, important antigen binding cells that also produce cytokines and chemokines influencing other lymphoid cells and immune function in general. They are known to be essential for innate immunity.

Figure 1.

 Cellular and humoral components of the immune system, including immunoglobulin and antibody formation by B cells, cytokine production by activated T cells, including continuous immune cell lines, and phagocytic cells such as macrophages and dendritic cells (DCs), which may be modulated (increased, decreased or variable) by different drugs of abuse. Cytokines produced by Th1 and Th2 helper cells as well as macrophages and DCs are often depressed, but sometimes enhanced.

As evident in Fig. 2, it is now recognized that drugs of abuse may affect many important components of the complex immune system, either enhancing or occasionally suppressing the function of distinct immune response cells and the factors they produce. In particular, many studies have documented that some of the drugs of abuse discussed in this review influence the lymphocytes as well as the macrophages and dendritic cells which produce a variety of factors necessary for a functional immune response. Numerous studies have now shown that various drugs of abuse affect naive T helper cell divergence into subtypes known to produce distinct cytokines necessary for humoral vs. cellular immune responses. This may occur because such drugs can bias the Th1 helper cell pathway, associated with effective antimicrobial activity, to the Th2 helper cell subset, important for humoral immunity but not protective against intracellular pathogens, which often are the major cause of infectious diseases in drug abusers (Fig. 1).

Figure 2.

 Drugs of abuse affect T helper cell biasing. Microorganisms stimulate different dendritic cell subclasses (DC1 or DC2) to produce cytokines, which activate naive precursor CD4+ T helper cells to differentiate into either Th1 or Th2 helper cells, which then regulate either cell-mediated or humoral immunity and the factors they produce, such as cytokines including interferon (IFN) γ, IL-12, and IL-12 receptors, signal transducer and activators of transcription 4 and 6 (STAT4 and 6), GATA3, tumour necrosis factor beta and immunoglobulins, etc.

Abuse substances such as opiates, cocaine, marijuana and alcohol, as well as nicotine in tobacco smoke, have all been reported to affect immune responsiveness. In most industrialized western countries such as the USA, opiates, including heroin, cocaine and, in some countries, even marijuana, are illegal but have been extensively studied for immunomodulatory effects on the host. Furthermore, legal drugs such as alcohol and nicotine in cigarette smoke are also immunomodulatory and markedly affect host immune resistance to microorganisms. The recreational use of such drugs has aroused serious concerns in recent years about the consequences for resistance to common and not so common microorganisms (Mansell, 1984; Siegel, 1986; Wagner et al., 1992; Lyman, 1993; Friedman, 1996; Dingle & Oei, 1997). In particular, numerous clinical studies have shown that an illegal drug of abuse may increase host susceptibility to infections and of mechanisms involved. In addition, excessive use of legal addictive psychoactive substances, including alcohol and cigarettes containing nicotine, correlates with major health problems, including infectious diseases.

Studies concerning the effects of addictive drugs on immunocompetence have taken on a greater urgency with the onset and explosive expansion of the worldwide pandemic of AIDS caused by HIV, which results in the collapse of the immune system, rendering individuals highly susceptible to opportunistic microorganisms that normally would not cause life-threatening infections. Various reports suggest that such drugs of abuse may be possible co-factors in the more rapid progression of AIDS, by virtue of their altering susceptibility to infectious diseases (Mansell, 1984; Siegel, 1986; Wagner et al., 1992; Lyman, 1993; Friedman, 1996; Dingle & Oei, 1997). This review discusses the nature and newer knowledge of some of the mechanisms of immunomodulation resulting in increased susceptibility to infection induced by illegal drugs, such as cannabinoids present in marijuana products, opiates such as morphine, and cocaine, as well as similar immunomodulation and decreased resistance to infection caused by legal drugs such as alcohol and nicotine in cigarette smoke.

Cannabinoid-induced immunomodulation and susceptibility to infection

Cannabis sativa, also known as marijuana, is the most frequently used illicit drug in the Western world. Marijuana has been recognized for centuries as a therapeutic agent. It has been widely used as an analgesic, muscle relaxant, appetite stimulator and anticonvulsant. Chemically, marijuana contains over 400 compounds, of which more than 60 are psychoactive cannabinoids, with the major component being delta-9-tetrahydro-annabinol (THC). Numerous studies over the last few decades have shown that cannabinoid components have marked immunomodulatory effects (Baczynsky & Zimmerman, 1983; Klein et al., 1985, 1987; Kawakami et al., 1988; Klein & Friedman, 1990; Djeu et al., 1991; Kaminski et al., 1994; Friedman et al., 1996, 2003, 2005). For example, cannabinoids alter the normal function of T and B lymphocytes, natural killer (NK) cells and macrophages, both in vitro and in vivo in humans and experimental animals (Tables 1 and 2). Although the molecular and cellular mechanisms for these effects are not completely defined, it is believed that both receptor and non-receptor mechanisms are involved. Two major cannabinoid receptors have been extensively studied (Mechoulam et al., 1969; Morahan et al., 1979; Mishkin & Cabral, 1985; Cabral et al., 1986; Ashfaq et al., 1987; Matsuda et al., 1990; Specter et al., 1991; Munro et al., 1993; Paradise & Friedman, 1993; Klein et al., 1993, 2000; Newton et al., 1994). The receptors CB1 and CB2 have been purified and shown to be G-protein-coupled 7-transmembrane molecules. The CB1 receptor is expressed mainly in the brain and certain peripheral tissues and is primarily responsible for psychoactive neurologic effects. CB2 receptors are located in the periphery, especially on immune cells. Analysis of these cannabinoid receptors (CBRs) led to the identification of endogenous cannabinoids that bind these receptors, and these are known as eicosanoides. The binding of CB1 receptors on central nervous system (CNS) cells, as well as CB2 receptors on immune cells, is involved in decreasing host resistance to bacterial and viral infections, as shown by various studies with THC and other cannabinoids in experimental animals and lymphoid cells, both human and from animals (Djeu et al., 1991).

Table 1.   Cannabinoid-induced immunosuppression
Immune functionIn vivoIn vitro
  1. +++, strongly decreased;

  2. ++,moderately decreased;

  3. ±, variable.

Humoral Ab formation+++++
Cytokine formation±±
Cellular immunity++++
Lymphocyte proliferation±+++
NK cells±++
Antimicrobial immunity++++
Cell signaling±±
Table 2.   Cannabinoid-induced modulation of immune function
Mode of administrationImmune activityEffect
In vivo
 HumanAntimicrobial activityDecreased
Cellular immunityDecreased
Humoral immunityDecreased
Serum Ig levelsVariable
In vitro
 HumanLymphocyte proliferationDecreased
NK cell activityDecreased
Neutrophil functionDecreased
Cytokine productionVariable
 MiceLymphocyte proliferationDecreased
NK cell activityDecreased
Antibody formationDecreased
IL-2 system receptorsDecreased
Cytokine productionVariable
ApoptosisIncreased
Cell signallingVariable

Historically, THC was first isolated and subsequently synthesized several decades ago, and it has been shown that treatment of animals in vivo or of lymphoid cells from humans or animals in vitro suppresses many immune functions, including lymphocyte proliferation, antibody formation and cytotoxic activity, as well as the production and activity of immune function requiring cytokines and/or chemokines (Djeu et al., 1991; Kaminski et al., 1994). Although there are still major gaps in our understanding of the cellular and molecular mechanisms whereby cannabinoids affect immunity and resistance to microbial infection, it is believed that at least some effects are mediated directly by the binding of the cannabinoid to CBRs, especially CBR2. Host immunity to microorganisms, however, involves many cell types, both immune and non-immune, as well as soluble mediators such as cytokines, chemokines, and hormones related to the hypothalamus–pituitary axis (HPA) of the neurologic system and neurocytokines.

Various studies during the last decades have shown that cannabinoids have marked effects on resistance to infectious diseases, both intracellular opportunistic bacteria and a wide variety of viruses (Morahan et al., 1979; Mishkin & Cabral, 1985; Cabral et al., 1986; Ashfaq et al., 1987; Specter et al., 1991; Paradise & Friedman, 1993; Klein et al., 1993, 2000; Newton et al., 1994, 1998). For example, laboratory studies with rodents have shown that specific cannabinoids alter susceptibility to intracellular bacteria such as Listeria, Legionella, and even Treponema pallidum, the etiologic cause of syphilis, as well as to the herpes simplex virus, and, although still controversial, they may contribute to the more rapid progression of HIV-infected individuals to clinical AIDS and to increased susceptibility to opportunistic microbial infection (Table 3).

Table 3.   Cannabinoid effects on in vivo resistance to infections
Infectious agentHost speciesEffect
  1. HSV, Herpes simplex virus.

HSVMiceMortality increased
ListeriaMiceInfection increased
Legionella sp.MiceInfection increased
StaphylococciRatsInfection increased
HSVHumanRecurrence increased
HIVHumanMortality risk increased
HSVGuinea pigsInfection increased
Treponema pallidumRabbitsProgression increased

Detailed studies have been performed with a number of model microbial organisms, especially the opportunistic intracellular bacterium Legionella pneumophila (Lp), a ubiquitous intracellular microorganism known to be the etiologic agent of Legionnaires' disease. Th1-cell-mediated immune responses are crucial for resistance to and recovery from Legionella infection, whereas Th2 responses, important for humoral immunity, are non-protective for resistance against intracellular bacteria or even viruses. Detailed studies have shown that THC treatment of mice infected with Legionella affects both innate and adaptive immunity (Bryant et al., 1987; Klein et al., 1993, 2000; Newton et al., 1994). For example, mice given a THC injection one day before and one day after sublethal challenge infection with L. pneumophila develop high levels of proinflammatory cytokines and rapidly die of septic shock. Enhanced proinflammatory cytokine production is lethal when animals are treated with THC or other highly active cannabinoid analogues such as the agonist Cp 55,940.

A single injection of THC in mice together with Legionella infection inhibits the development of Th1 immunity involving both CB1 and CB2 receptors (Newton et al., 1994). The effects of THC on Th1 cell development involve suppressed production of IFNγ and IL-12, important for the development of host immunity to intracellular microorganisms such as Legionella. Decreased cellular immunity to Lp infection by THC treatment is not only mediated by a decrease in IL-12 and its receptor but also by a concomitant increase in IL-4 and the transcription factor GATA-3, now known to be important for Th2 cell activity. Other important mechanisms are now recognized that drive Th1 cell polarization, including production by dendritic cells of cytokines such as IL-12 and IL-13 and chemokines such as CCL3 and CXCL10, as well as co-stimulatory receptors and ligands on these cells such as CD40, NOTCH ligands and TOLL-like receptors.

Recent studies have shown that Lp infection induces IL-12 in mouse bone-marrow-derived dendritic cells (DCs), as well as in mouse and human DCs that express cannabinoid receptors and are activated by cannabinoids, supporting the view that cannabinoids polarize to Th2 immunity by affecting DC function following Lp infection. This suggests that cannabinoid receptors on DCs, now known as the major antigen-recognizing cells essential for both innate and adaptive immunity, are involved. This effect of cannabinoids appears more general than purely host resistance to microbial infection, because the effects of THC on shifting protective Th1 host responses have been reported in animal models of tumour immunity after treatment with a cannabinoid. Thus cannabinoids, including THC, can compromise the immune system to favour a Th2-mediated response, which is ineffective against intracellular microorganisms.

Effects of opiates on immunity and susceptibility to infections

Psychoactive drugs such as opium, morphine and heroin are derived from Papaver sonniferum (Scott, 1969). Opiates, in particular, have had a major impact on the history of mankind, in terms both of drug abuse and wars for opium control (Risdahl et al., 1996). There is, for example, evidence of widespread poppy cultivation during the Stone Age. The term opium is derived from the Greek word meaning ‘juice’, since the drug is obtained from the juice of the poppy plant. In recent centuries the addictive nature of opium has been recognized, and in the early 1800's morphine and later codeine, heroin and other opium alkaloids were synthesized from opium and often used medicinally. It was recognized about a century ago, however, that microbial infection was a serious complication of opiate addiction. In the late 19th century, clinical observation provided evidence that morphine altered the normal host physiological responses necessary for resistance to infection, and it became evident that opiate use contributed to infectious disease (Bryant et al., 1987; Risdahl et al., 1998). It is now widely recognized that opiates, including morphine, are immunomodulatory and enhance susceptibility to various infectious agents in both humans and animals. For example, pulmonary infections caused by mycobacteria, staphylococci, streptococci, hemophilus and other common organisms occur frequently in opiate abusers (Friedman et al., 1994, 2003, 2005; Almirall et al., 1999). Intravenous (i.v.) drug abusers become highly susceptible to HIV not only because of contaminated shared needles but also because of associated immunosuppression (Battjes et al., 1988; Donahoe & Falek, 1988). Serious endocarditis caused by organisms as diverse as staphylococci, enterococci, pseudomonas, klebsiella, serratia and Candida, cellulitis caused by staphylococci, streptococci, hemophilus and similar bacteria, as well as hepatitis A, B and C, and sexually transmitted infections that are bacterial, viral and parasitic, have also been shown to be increased in individuals addicted to opiates.

Studies over the past few decades have shown that opiates markedly affect many immune responses, both in vivo and in vitro, in animal models such as rodents and mice, and even in monkeys and swine, including altered resistance following challenge infection with a microorganism. Moreover, opiates given either medicinally or to addicts have marked immunomodulatory effects (Table 4). In addition, studies in numerous laboratories with a variety of opiate preparations administered to animals in vivo or added to lymphoid cell cultures in vitro have shown marked effects on immune function, providing convincing evidence of immunomodulatory effects (Table 4).

Table 4.   Opiate-induced immune function modulation in vivo and in vitro
Mode of administrationImmune functionActivity
  1. CTL, cytotoxic lymphocytes ; PMN, polymorphonuclear.

In vivo
 RodentsPhagocytosisDecreased
Antibody productionDecreased
Mitogen proliferationDecreased
NK/CTL activityDecreased
Cytokine productionDecreased
Cytokine levelsIncreased
LPS-induced sepsisIncreased
Cutaneous hypersensitivityDecreased
 HumansPhagocytosisDecreased
NK activityDecreased
Cell cytotoxicityDecreased
 MonkeysChemotaxisDecreased
PMN killingDecreased
 PigsCutaneous hypersensitivityDecreased
In vitro
 MicePhagocytosisDecreased
Cell proliferationDecreased
Antibody productionDecreased
Cytokine productionDecreased
ChemotaxisDecreased
Superoxide productionDecreased
Cytokine productionVariable
Chemokine productionVariable

There is much interest in determining the mechanism by which opiates affect the immune response, especially in regards to altered host resistance to infectious agents. Several opiate receptors have been identified on cells of the nervous system of animals and humans, with mu, kappa (k) and gamma (g) subtypes predominating (Tubaro et al., 1983; Bryant & Roudebush, 1990; Adler et al., 1993; Reisine & Bell, 1993; Mellon & Bayer, 1998; Roy et al., 1998; Carthy et al., 2001; Rahim et al., 2001). These classical opiate receptors, similar to cannabinoid receptors, are G-protein-coupled 7-transmembrane molecules. Opiates directly ligate mu and g opiate receptors as well as nonclassical opiate-like receptors on immune cells, and also bind to similar receptors on CNS cells. Studies in vitro with opiate-treated immune cells showed that receptor-mediated suppression of macrophage phagocytosis, chemotaxis, cytokine and chemokine production occurs rapidly. These effects are linked to the modulation of host resistance to bacterial, viral, fungal and protozoan infections using animal models in vivo and immune cells in vitro, including cell lines and primary cell cultures (Allolio et al., 1987; Bryant & Roudebush, 1990; Bayer et al., 1990, 1992; Bussiere et al., 1992; Molitor et al., 1992; Chao et al., 1993; Bhargava et al., 1994; Alicea et al., 1996; Eisenstein et al., 1996; Houghtling et al., 2000a, b; Roy et al., 2005, 2001).

While opiates are known to modulate host immune responses directly, their effects on the physiological function of nonspecific host mechanisms and altered immune responses play an important role in increased susceptibility to infection. Many effects arising from direct interaction with cells of the nervous system, especially via the HPA by stimulating the release of cortitropin-releasing hormone and adrenocotropic hormone, result in an increase in serum levels of glucocorticoid and corticosterone, hormone factors from the HPA. Glucocorticoids, in particular, have an important role in regulating cellular immune responses and suppress many immune parameters.

Corticoid-induced immunosuppression through the autonomic nervous system also occurs (Allolio et al., 1987). For example, NK cell activity in experimental animals is also suppressed by interaction with opiate receptors following morphine injection into the lateral ventricle of the rat brain (Bayer et al., 1990, 1992; Chao et al., 1990; Vlahov et al., 1991; Risdahl et al., 1993; Szabo et al., 1993; Peng et al., 2001; Roy et al., 2001). It is now evident that the effects of opiates on CNS pathways include the suppression of lymphocyte activation and function. Increased production of immunosuppressive cytokines such as TGFβ by morphine-treated immune cells is another indirect method by which opiates suppress immunity (Peng et al., 2001). Opiate-induced immunomodulation occurs by both direct and indirect mechanisms involving receptors on both CNS and immune cells.

Various studies in recent years have shown that increased susceptibility to microbial infections is evident in experimental animals given opiates (Table 5). Many animal studies have been performed with bacteria such as Escherichia coli and Salmonella typhimurium, the fungi Candida albicans and Toxoplasma gondii, and viruses such as the herpes virus and Friend leukemia virus (Chao et al., 1990; Starec et al., 1991; Vlahov et al., 1991; Risdahl et al., 1993; Szabo et al., 1993; Peterson et al., 1995; Farlane et al., 2000; Bangsberg et al., 2002; Feng et al., 2005; Wang et al., 2005). Much information concerning the nature and mechanisms of the immunomodulatory effects of opiates and altered susceptibility to common opportunistic intracellular microbial organisms important in opportunistic infections has been discovered. For example, recent studies have shown that oral infection of mice with sublethal numbers of Salmonella can be enhanced by implanting pellets containing slow-release morphine. The increased lethality by sublethal challenge with small numbers of bacteria was related to decreased immune function (Feng et al., 2005). However, when morphine was administered by a mini-pump there was no significant increase in susceptibility to similar oral Salmonella infection, even though the immune response was suppressed. Furthermore, there was a disconnect between gastrointestinal mobility and transmigration of the Salmonella through the gastric tract in the morphine-pellet-implanted mice vs. mice given morphine by a mini-pump, indicating that morphine effects on susceptibility to microbial infection are more complex than merely depressing the function of host immune cells.

Table 5.   Opiate effects on microbial infection in animal models
MicroorganismActivity increased
Salmonella typhimuriumGut colonization
Toxoplasma gondiiLethality
Escherichia coliSepsis
HSV-1Lethality
FLVLethality
Candida albicansLethality
Swine herpesvirusLethality

It is evident that chronic morphine treatment alters a number of immune parameters involved in cellular immunity important for resistance to infectious diseases. For example, chronic morphine treatment impairs cellular immunity by altering the differentiation of Th1 helper cells, which is generally similar to what occurs in cannabinoid treatment (Roy et al., 2001). In vitro studies have shown that morphine directs CD4+ T helper cells towards Th2 differentiation, and this is related to the modulation of ‘transcriptional switches’ GATA-3 and T-bet, again similar to what occurs with cannabinoids (Roy et al., 2005). These transcriptional factors differentially select Th1 vs. Th2 activity. Thus morphine directs CD4+ differentiation in a similar way to cannabinoids, and such findings concerning the molecular mechanisms by which morphine affects the immune response suggest that therapies that prevent Th2 differentiation and promote Th1 cytokine synthesis would be beneficial in immunosuppressed drug-abuse populations.

Cocaine and infectious diseases

Cocaine used by i.v. drug abusers has been linked to increased incidence of HIV seroprevalence and progression of AIDS (Chaisson et al., 1989; Anthony et al., 1991; Peterson et al., 1991; Bagasra & Pomerantz, 1993; Baldwin et al., 1998). Cocaine increases HIV replication in peripheral blood mononuclear cells (PBMCs) in vitro, and also increases viral load in experimental immunodeficient mice transplanted with human PBMCs, as well as decreasing immune responses to challenge antigens and decreasing the CD4 : CD8 ratio as markers of immune function (Bagasra & Forman, 1989; Chaisson et al., 1989; Anthony et al., 1991; Peterson et al., 1991; Bagasra & Pomerantz, 1993; Liu et al., 1995; Baldwin et al., 1998; Matsumoto et al., 2002; Maurice et al., 2002). Immunomodulation induced by cocaine appears to be related to specific receptors in the periphery as well as the CNS. Cocaine-induced suppression of mitogen-stimulated lymphoproliferation occurs. Because of the possible link of cocaine use to AIDS, there is increasing interest in understanding the mechanism(s) by which cocaine affects immunity and alters susceptibility to infectious diseases. Because cocaine is a water-soluble alkaloid, it is readily absorbed through mucous membranes. It is now recognized that the activity of cocaine is the result of effects at least partially mediated through the sigma 1 receptor, first proposed to be involved with morphine binding (Chiasson et al., 1991; Su, 1991; Sopori & Kozak, 1998; Sopori et al., 1998; Hakki et al., 2000; Hallquist et al., 2000; Matsunaga et al., 2001; Pellegrino et al., 2001; Sopori, 2002; Slavinsky et al., 2002; Matsumoto et al., 2002; Maurice et al., 2002; Ouyang et al., 2000). This receptor is distributed throughout the brain and nervous tissue of an individual, similar to classic opiate and cannabinoid receptors. Most studies concerning the mechanisms of the immunomodulatory effects of cocaine related to increased susceptibility to infections have centred on HIV and progression to AIDS (Chaisson et al., 1989; Chiasson et al., 1991; Peterson et al., 1991; Bagasra & Pomerantz, 1993; Baldwin et al., 1998). However, some in vivo and in vitro studies have addressed cocaine-induced modulation of immune responses and other infection model systems.

Extensive studies have been performed in recent years on rodent models treated with cocaine in regards to the effects on immune responses in general, including responses such as antibody formation, T-cell-mediated cellular immunity and macrophage activation. In general, cocaine markedly decreases immune parameters or, at least, has variable effects. Humans administered cocaine, with or without morphine, show increased susceptibility to infection and marked depression of immune competences, both cellular and humoral, after specific microbial challenge. It should be noted that the mechanisms of the effects of cocaine on immunity have been studied most extensively in rodent models and with lymphoid cell cultures in vitro. Nearly all reports have shown a decrease of the immune function examined (Table 6).

Table 6.   Cocaine-induced immune modulation
Mode of administrationActivityEffect
In vivo
 HumansAntimicrobial activityDecreased
Cytokine productionVariable
 RodentsLymphocyte proliferationDecreased
Antibody formationDecreased
Cellular hypersensitivityDecreased
Th1/Th2 cellsVariable
Cytokine productionVariable
In vitro
 HumansHIV replicationIncreased
Lymphocyte proliferationDecreased
Cytokine productionDecreased
 RodentsCytokine productionDecreased
Lymphocyte proliferationDecreased
NK cell activityDecreased

Nicotine-induced immunomodulation and susceptibility to infection

It is widely accepted that cigarette smoking is linked to community-acquired pneumonia and is one of the major risk factors for respiratory infections. Cigarette smoke is composed of two components, namely the vapour and the particulate phase. The immunomodulatory effects of tobacco smoke are mainly the result of the major addictive component, nicotine, which occurs in the particulate portion. Nicotine is a small organic alkaloid synthesized by the tobacco plant and now recognized as the major addictive component of cigarettes. While its small molecular nature allows nicotine to cross directly through cell membranes, the primary biological effects are receptor-mediated. Nicotine is an agonist for nicotinic acetylene receptors (nAChRs) present on cells of the nervous system as well as other cells throughout the body, including immune cells (Sopori & Kozak, 1998; Sopori et al., 1998; Hakki et al., 2000; Hallquist et al., 2000; Matsunaga et al., 2001; Sopori, 2002). Neuronal AChRs are known to be upregulated in smokers. Nicotine from cigarette smoke rapidly accumulates in the brain and increases dopamine transmission within the shell of the nucleus accumbens, the region of the brain associated with reward processing and also with the addictive properties of other drugs, including opiates, alcohol and cannabinoids.

Nicotine and cigarette smoke have marked effects on the immune response system (Sopori et al., 1998; Sopori, 2002). There is increasing evidence that nicotine induces glucocorticoid release via the HPA and directly affects cells of the immune system through ligation of nAChRs on CNS and immune cells. Nicotine inhibits the production of cytokines such as IL-6, TNFα and IL-12. Depressed murine alveolar macrophage function after infection with L. pneumophila occurs via specific interaction with the acetylenecholine receptor (Ouyang et al., 2000). Interaction with this receptor by nicotine affects splenocyte production of Th1- and Th2-defining cytokines induced by various lymphocyte activators, such as mitogens (Slavinsky et al., 2002).

Chronic nicotine treatment of rats induces T cell anergy, depletes intracellular IP3 and intracellular Ca2+ stores, and inhibits antibody-forming cell responses and lymphocyte proliferation, contributing to suppressed protective immune responses to microbial antigens in experimental animals (Sopori & Kozak, 1998; Sopori et al., 1998; Sopori, 2002). For example, exposure of animals to cigarette smoke in inhalation chambers results in increased susceptibility to infections by various bacteria and viruses (Table 7). Cigarette smoking has been related to increased susceptibility to microbial infection in HIV-positive individuals (Slavinsky et al., 2002). Understanding the mechanisms by which nicotine, a widely used legal addictive drug delivered by cigarette smoking, increases or alters susceptibility to infectious diseases is important. Other studies on the nature and mechanisms of the immunomodulatory effects of nicotine and its interactions with specific receptors are warranted, especially because of the recognition of increased susceptibility to many environmental opportunistic microorganisms in the general population.

Table 7.   Effects of nicotine and cigarette smoke on host resistance mechanism
Host speciesImmune functionsEffect
In vivo
 RatsAntibody formationDecreased
Intracellular Ca++storesDecreased
Lymphocyte proliferationDecreased
T-cell anergyIncreased
Antimicrobial activityDecreased
In vitro
 HumansNK activityDecreased
Cytokine productionDecreased
 MiceSplenocyte proliferationDecreased
Cytokine productionVariable
Infection susceptibilityIncreased

Alcohol-induced susceptibility to infections

Alcohol abusers are known to experience a variety of health problems, including decreased liver function and especially increased rates of infectious diseases, including community-acquired pneumonia (Adams & Jordan, 1984; Bermudez & Young, 1991; Alak et al., 1993; Cook, 1998; Bautista, 2001; Cook et al., 2002; Gao, 2002; Jerrells, 2002a, b). Moderate alcohol use (one beer, one glass of wine or one mixed drink per day) is thought by some physicians to be beneficial, but excessive use of alcohol is known to be detrimental to health. Alcohol, unlike other addictive drugs of abuse, does not appear to bind to a specific receptor. Alcohol has multiple effects on host immune responses to microbial pathogens, including depletion of circulating lymphocyte populations and altered lymphoid organ architecture and immune function (Table 8). Furthermore, studies on both animals and humans have shown that in vivo as well as in vitro exposure to alcohol suppresses production of cytokines important for antimicrobial immunity, such as TNFα secreted by macrophages from rats, Rhesus monkeys and macaques (Bermudez et al., 1991; Jerrells et al., 1992; Sibley & Jerrells, 2000; Stoltz et al., 2000; Sibley et al., 2001; Nelson & Kolls, 2002). Suppression of TNFα is a post-transcriptional event and involves TNFα converting enzyme (TACE)-mediated alterations of TNFα. Furthermore, alcohol inhibits LPS-induced NFκβ activation, a transcription factor for inflammatory cytokines. Of particular interest are reports that frequent alcohol use decreases the Th1 cytokine responses important for protection against microbial infection and increases Th2 cytokines, which are generally not protective (Bermudez et al., 1992; Szabo et al., 2001). Administration of IL-12, a cytokine important for Th1 activity, attenuates suppressed cell-mediated immune responses in alcohol-consuming mice.

Table 8.   Alcohol-induced immunomodulation
Host speciesImmune functionsEffect
In vivo
 MiceCytokine productionDecreased
NK activityDecreased
IgA and IgG productionDecreased
ApoptosisIncreased
Cellular hypersensitivityDecreased
 RatsTNFα processingDecreased
Alveolar nitric oxideDecreased
Chemokine productionDecreased
 HumansMonocyte proliferationDecreased
In vitro
 MiceMacrophage killingDecreased
Bactericidal capacityIncreased
Cytokine productionDecreased
 HumansMacrophage killingDecreased
Cytokine productionVariable
TNFα receptorDecreased
NFκB activationDecreased
T-cell proliferationDecreased
 Rhesus macaquesTNFαDecreased

Rodents given alcohol orally show a marked decrease of immune cell function and increased susceptibility to infections. For example, ethanol treatment of mice enhances intracellular survival of mycobacterium avian complex and compromises macrophage responses to cytokines. Ethanol treatment also depresses resistance to microorganisms such as streptomycin by growth of L. pneumophila in otherwise nonpermissive macrophage cultures in vitro (Chahbazian et al., 1992; Yamamoto et al., 1993). Extensive studies have shown that immune cells from mice given alcohol and infected with intracellular bacteria such as salmonella or listeria have increased susceptibility to the bacteria. Excessive alcohol abuse has been linked to increased viral infection, including herpes virus infection in adolescent females. Furthermore, experimental studies show that alcohol alters cytokine responses of mice infected with the retrovirus that causes a murine AIDS-like disease (Wang et al., 1993, 1997; Wang & Watson, 1994). However, it is not clear whether alcohol is a co-factor for more rapid AIDS progression in humans as is the case for cocaine, opiates and marijuana. Besides the reported studies that alcohol exacerbates opportunistic infections in the murine AIDS, increased opportunistic infections because of alcohol appear correlated with AIDS progression. In addition, hepatitis B virus infection has been linked to chronic liver disease in alcoholics, and animal studies show that alcohol enhances liver damage by activating CD8+ cells and increases apoptosis. Thus, animal models and clinical studies both indicate that alcohol abuse is clearly detrimental and related to increased susceptibility to microbial infection.

Discussion and conclusions

The use of addictive drugs of abuse, such as opiates, marijuana and cocaine, has been linked to increased susceptibility to infectious diseases, including AIDS (Mansell, 1984; Ruiz et al., 1999; Friedman et al., 2003, 1996). Clinical and experimental animal studies, both in vivo and in vitro, indicate that the abuse of such drugs by individuals is associated with enhanced susceptibility to infectious diseases. One mechanism by which these drugs of abuse affect immunity indirectly is stimulation of the HPA, resulting in glucocorticoid production and dysregulation of the immune system. Direct effects on immune cells involve ligation of specific receptors that affect immune responses in both animals and humans so as to alter susceptibility to infection. The involvement of specific receptors has been studied in detail for many years, first with opiates and more recently with cannabinoids and nicotine.

It is now widely accepted that common mechanisms are involved in the immunomodulatory effects of illegal drugs of abuse, especially effects on Th1/Th2 responses such as inhibition of Th1- or elevation of Th2-associated cytokines (Bussiere et al., 1992). Similar studies with the legal drugs nicotine in cigarette smoke and alcohol have also related alterations of immune responses to increased susceptibility to infections in those abusing alcohol or smoking cigarettes. Nicotine effects have been related to specific interactions with acetylcholine receptors in the CNS and periphery. Alcohol-induced immunosuppression, however, does not appear to be receptor-mediated.

The apparent causal correlation between the intravenous abuse of drugs and susceptibility to HIV infection or progression has led many investigators to propose that the immunomodulation mediated by such drugs is an important factor contributing to susceptibility and progression of AIDS (Mansell, 1984; Siegel, 1986; Panaslak et al., 1990; Lyman, 1993; Nieman et al., 1993; Wang & Watson, 1994; Friedman, 1996; Friedman et al., 1996; Dingle & Oei, 1997; Wang et al., 1997; Meyerhoff, 2001; Grimm et al., 1998). However, it is not yet possible to determine a definitive cause-and-effect relationship from epidemiologic studies, although there is a growing consensus among drug-abuse investigators that effects on the immune system resulting in immunomodulation are involved. The many recent studies on immunosuppression by such drugs in experimental animals support the view that increased susceptibility to opportunistic infectious pathogens is related to the alteration of immune responses caused by the drug. There is still convincing evidence, however, that the behavioural and social practices associated with drug abuse apart from immunomodulation contribute to increased exposure to infectious pathogens and opportunistic infections. Nevertheless, many investigators believe it probable that a combination of increased exposure to microorganisms and drug-abuse-induced immunomodulation contributes to the heightened susceptibility to infectious pathogens, including HIV. Thus, there is a general consensus by investigators, both clinical and basic scientists, that it is essential to determine in depth the mechanisms by which drugs of abuse, both illicit and legal, compromise immune responses in general, especially in concert with immunosuppressive viruses.

Acknowledgements

Research results from the authors' laboratories were supported in part by grants from the US National Institutes of Health. The authors acknowledge with thanks the valuable assistance of Catherine Newton, and Amal Hakki's excellent assistance in the studies described from the authors' laboratories.

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