الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Substance abuse is a complex physiologic, social and behavioral disorder that often coexists with psychiatric illness as well as comorbid medical conditions. Chronic drug use and abuse has been documented to result in severe immune consequences and thus may pose a significant risk factor to opportunistic infection. It is, therefore, not surprising that epidemiological studies show increased prevalence of such infections as tuberculosis, HIV and pneumonia among drug abusers. Besides sharing unsterilized and contaminated needles, the occurrence of infection in these patients has been largely attributed to immunomodulatory effects of abused drugs. Defense against microbes is known to be mediated by a combination of both the early innate as well as the late adaptive immune reactions. Chronic drugs have been shown to affect both arms of immune defense mechanisms.
Opiates compose a collection of drugs derived from the poppy Papaver somniferum which include opium, morphine, and heroin. Opium was derived from the Greek word meaning “of sap” or “juice”, because the drug is obtained from the juice of the poppy plant. Most studies indicate that morphine acts on central µ opioid receptors and activate the hypothalamic–pituitary–adrenal (HPA) axis, resulting in the release of glucocorticoids from the adrenal cortex. It has been suggested that whereas chronic morphine treatment induces immunosuppression through glucocorticoids, the immunosuppressive effects of acute morphine administration seem to be glucocorticoids-independent.
Chronic morphine treatment temporally inhibits Th1 cytokines such as IL-2 IL-12 and IFN-γ and increases Th2 cytokines IL-4 and IL-5 and IL-10, both at the transcription and protein synthesis level. It has bee further demonstrated that chronic morphine treatment polarizes naive CD4+ T cell differentiation toward Th2 through an adenylate cyclase-mediated mechanism. These effects were abolished in MORKO (µ opioid receptor knock out) mice implicating a distinct role for the µ opioid receptor in this function.
These observations might have clinical significance and implications since Th1/Th2 cytokine imbalance in hosts is associated with increased susceptibility to infection by intracellular microbes. Appropriate induction of a Th1 differentiation is necessary for an effective response to intracellular pathogens and involves macrophage activation, efficient NK and CTL cytotoxic activities as well as the production of complement fixing and opsonizing antibodies.
In experimental models, morphine has been shown not only to induce the degradation of the host defense barrier but also to potentiate the effects of the B cell mitogen LPS. Several studies show that morphine synergized with LPS and augmented the secretion of both IL-6 and TNF-α. Expression of these cytokine genes is dependent on the activation of a transcription factor, NF-κB. It was also demonstrated that opiate derivatives are capable of preventing LPS-induced septic shock mortality by indirect inhibition of TNF-α production in vivo.
Marijuana is the common name for Cannabis sativa, a plant that has long been known for its “medicinal” and recreational properties and for its fiber (hemp). Chemical extracts of marijuana contain over 400 compounds and more than 60 cannabinoids. Cannabinoids, especially the major psychoactive component Δ9-tetrahydrocannabinol (THC), exert immunomodulatory effects that alter normal functions of T and B lymphocytes, NK cells, and macrophages in human and animals. These modulations have been observed during both in vivo and in vitro cannabinoid treatment.
In addition, THC was noted to suppress mouse splenocyte T lymphocyte proliferation in response to the T cell mitogens Con A and PHA as well as that of B lymphocytes induced by the bacterial lipopolysaccharide (LPS). Cannabinoids have also been reported to suppress a variety of the activities of T lymphocytes. For example, it was reported that the cytolytic activity of murine cytotoxic T lymphocytes (CTLs) generated by co-culture with either allospecific or TNP-modified self stimulators was suppressed by THC and 11-hydroxy-THC. Allospecific CTLs generated in vivo also were inhibited by in vitro exposure to these cannabinoids. It has also been shown that THC decreased the CTL activity against virus-infected cells and inhibited the CTL cytoplasmic polarization towards the virus-infected target cells both in human and murine hosts.
NF-κB is a group of pleiotropic transcription factors activated by numerous stimuli (~460 and still counting). Studies in the past decades have uncovered multiple new pathways and new mechanisms regulating NF-κB activity. In addition to the canonical pathways, NF-κB activity is regulated by multiple non-canonical pathways that lead to NF-κB activation without involving IKK activation, IκB serine phosphorylation, and proteasomal degradation.
NF-κB proteins are constitutively expressed in all cell types with the exception of RelB, the expression of which is restricted to lymphoid tissues. Although most NF-κB dimmers are activators of transcription, p52/p52, p50/p50, and p65/p65 homodimers are transcriptional repressors. Most studies addressing the immunosuppressive consequences of drug addiction has been performed using purified cannabinoids and opiates or their derivatives. Chronically exposed drug abusers, however, tend to use a mixture of drugs that may vary in constitution at different times during their addiction life. In addition, a substantial sector of drug addicts may pass through intermittent periods of drug withdrawal. This is why it seems difficult to directly link specific drugs of abuse to the observed state of immunosuppression and the subsequent clinical health parameters.
This work aims at studying the effect of opiate and cannabinoid addiction on polyclonal T cell proliferation as a pivotal event in cell-mediated immunity to infection with assessment of the effects of drug addiction on the cytoplasmic NF-κB activity in mitogen stimulated lymphocytes and correlate all these parameters with the type of the abused drug.
The study was conducted on a total of 45 Egyptian opiate and cannabinoid addicts recruited from the outpatient Clinic of the department of Psychiatry, Main University Hospital, University of Alexandria. The type of the drug abused (either cannabinoid or opiate) was qualitatively screened in urine samples of addicted persons using commercially available kits. Following drug identification heparinized peripheral blood samples were obtained from all subjects under study and were used for preparation of sufficient amounts of PBMCs. Peripheral blood lymphocytes obtained from all subjects under study were maintained in a short term culture either in the presence or absence of PHA mitogenic stimulation. Extent of T cell proliferation, manifested by the metabolic activity of PBMCs following mitogenic stimulation, was monitored by the MTT cell proliferation detection kit and results were expressed as a stimulation index (S.I). Cultured lymphocytes were also tested for expression of the cytoplasmic fraction of the transcription factor NF-κB by ELISA using commercially available kits specific for the P50/65 heterodimers.
Statistical analysis of the results obtained in the present study revealed a significant impairment of T cell proliferation in both cannabinoid and opiate addicts as compared to their corresponding controls. In addition, there was also a significant reduction in T cell function in opiate abusers relative to cannabinoid abuse.
Our results revealed also a statistically significant increase of spontaneous and PHA-induced NF-κB levels in cannabinoid and opiate addicts when compared to their corresponding controls. There was also a significant increase in spontaneous NF-κB activity of cannabinoid abusers as compared to opiate addicts.
Concerning PHA-induced NF-κB, our results revealed that the significant increase was restricted only to abusers of cannabinoids when compared to both controls and opiate addicts while no significant change was recorded between opiate addicts and controls.
Regarding the interrelationship between spontaneous versus PHA-induced NF-κB activity within each of the studied groups, our results revealed no significant variation in control subjects while significant reduction in NF-κB activity was recorded within both abusers of cannabinoids and opiates.
Pearson correlation studies done among results of all parameters obtained for all subjects under study and revealed the following:
3- Significant positive correlation between spontaneous and PHA-induced NF-κB expression in cannabinoid addicts.
4- Significant positive correlation between spontaneous and PHA-induced NF-κB expression in opiate addicts.