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The suppressive effect of 1.0 mg/kg buprenorphine on IFN-g production is attenuated by administration of the opioid receptor antagonist, naltrexone. K.A. Carrigan et al., Int Immunopharmacol 2004, 4:419-428 0 CD4+ T lymphocytes are the primary cell target for human immunodeficiency virus-1 (HIV-1), and these cells are known to express opioid receptors. Due to the need for new treatment approaches to HIV-1 infection, we sought to determine whether the non-selective opioid receptor antagonist naltrexone would affect HIV-1 expression in CD4+ lymphocyte cultures and whether naltrexone would alter the antiviral properties of zidovudine (AZT) or indinavir. Activated CD4+ lymphocytes were infected with a monocytotropic or T-cell tropic HIV-1 isolate, and p24 antigen levels were measured in supernatants of drug-treated or untreated (control) cultures. While naltrexone alone did not affect HIV-1 expression, at a concentration of 10−12–10−10 M naltrexone increased the antiviral activity of AZT and indinavir 2–3-fold. Similar findings with a k-opioid receptor (KOR) selective antagonist supported the possible involvement of KOR in naltrexone’s potentiation of the antiretroviral drugs. The results of this in vitro study suggest that treatment of alcohol or opiate dependent HIV-1-infected patients with naltrexone is unlikely to interfere with the activity of antiretroviral drugs. Also, based upon naltrexone’s safety profile and its synergistic activity in vitro, these findings suggest clinical trials should be considered of naltrexone as an adjunctive therapy of HIV-1 infection. 1 The analgesic property of opiates has been known since ancient times. Only recently has an appreciation of the broad effects of opioids on the inflammatory response emerged. Acting largely through m-, k- and dopioid G protein-coupled receptors on T lymphocytes and macrophages, cognate ligands modulate many activities of these cells, including cytokine production. In addition to acting as chemotactic stimuli, opioids can, through the process of heterologous crossdesensitization, act as stop signals in leukocyte trafficking. When administered into the central nervous system, certain chemokines can “We propose that opioids should be considered members of cross-desensitize to the analgesic effect of opioids. We propose that opioids the cytokine familymembers and thatoffuture research opioids could should be considered the cytokine familyon and that future yield new foryield inflammatory and diseases, research ontherapies opioids could new therapies forinfectious inflammatory and including HIV-1 infection.” infectious diseases, including HIV-1 infection. 2 Opioid and chemokine receptor expression by T cells, monocytes, microglial cells and neurons. Neuron–microglial cell communication occurs through the release of various chemical mediators, including the production of CX3CL1 (fractalkine) by neurons and the production of additional chemokines, such as CCL3, CCL4 and CCL5, by microglial cells. The chemokines produced by microglial cells (and astrocytes) in the brain act as chemoattractants and/or activators of circulating T cells and monocytes. The production of CCL2 is a potent chemoattractant for the passage of monocytes through the blood–brain barrier. In addition, endogenous opioids, produced in the brain and by cells of the immune system, act to regulate circulating immune cells and microglial-cell inflammatory activities. 3 Model describing the influence of opioids on HIV replication. MOR activation of macrophages and potentially T cells and microglia initiates an increase in the expression of chemokines CCL2, CCL5 and CXCL10, which might act to attract susceptible T cells, monocytes and/or macrophages or microglia to the site of HIV infection. m-opioid receptor (MOR) ligands also signal an upregulation in the expression of the major HIV coreceptors CCR5 and CXCR4. By contrast, k-opioid receptor (KOR) activation directly (and probably indirectly) inhibits the expression of proinflammatory cytokines and chemokines. This results in a depressed state of cellular activation and reduced HIV replication. In addition, KOR signals an inhibition of the expression of CCR5 and CXCR4, leading to reduced HIV binding and reduced chemotaxis of potentially susceptible target cells. 4 m-Opioid modulation of HIV-1 coreceptor expression and HIV-1 replication Steele A.D, et al., 309:99–10 (2003) A substantial proportion of HIV-1-infected individuals are intravenous drug users (IVDUs) who abuse opiates. Opioids induce a number of immunomodulatory effects that may directly influence HIV-1 disease progression. In the present report, we have investigated the effect of opioids on the expression of the major HIV-1 coreceptors CXCR4 and CCR5. For these studies we have focused on opiates which are ligands for the m-opioid receptor. Our results show that DAMGO, a selective mopioid agonist, increases CXCR4 and CCR5 expression in both CD3+ lymphoblasts and CD14+ monocytes three- to fivefold. Furthermore, DAMGO-induced elevation of HIV-1 coreceptor expression translates into enhanced replication of both X4 and R5 viral strains of HIV-1. We have confirmed the role of the m–opioid receptor based on the ability of a mopioid receptor-selective antagonistato block them-opioid effects ofagonist, DAMGO. We “Our results show that DAMGO, selective have also found thatand morphine enhances CXCR4 and CCR5 expression + lymphoblasts increases CXCR4 CCR5 expression in both CD3 and subsequently increases both X4 and R5 HIV-1 infection. We suggest + monocytes and CD14 threefivefold. Furthermore, that the capacity of m-opioids to to increase HIV-1 coreceptorDAMGOexpression and induced of HIV-1 expression translates into replicationelevation may promote viralcoreceptor binding, trafficking of HIV-1-infected cells, enhanced replication both X4 and R5 viral strains of HIV-1.” and enhanced disease of progression. Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study Bouvard M.P., et al. The effect of month-long naltrexone (NTX) treatment at a daily oral dose of 0.5 mg/kg/day was contrasted with placebo (PLC) in a double-blind study with conjoint clinical and biochemical evaluations of therapeutic effects. Modest clinical benefits were achieved with both PLC and NTX, with marginally better overall results following NTX, and degree of improvement appeared to be related to plasma chemical profiles. Massively elevated levels of b-endorphin were observed in all children with assays using C-terminal antibody but not with an N-terminal antibody assay. In addition, 70% of the children exhibited abnormally low levels of adrenocorticotropic hormone, and smaller subsets exhibited elevated norepinephrine (6@%), arginine-vasopressin (SO%), and serotonin (20%). The best clinical responders exhibited the clearest normalization of the elevated plasma chemistries, especially in C-terminal&endorphin and suggest serotonin.that There wasonly some evidencea of therapeutic “The results NTX benefits subgroup of carry-over autistic effects in both clinical and biochemical measures in those children who received NTX children, identified by the certain ofplasma before PLC.who The may resultsbesuggest that NTX onlypresence benefits aofsubgroup autistic abnormalities. These results suggest a possible linkage between children, who may be identified by the presence of certain plasma abnormalities. abnormal especially related to chemistries, the proThese resultsplasma suggest chemistries, a possible linkage betweenthose abnormal plasma opiomelanocortin and autistic symptoms.” especially those relatedsystem, to the pro-opiomelanocortin system, and autistic symptoms. 6 Smith J.P., et al., 102:820–828, 2007 Low-Dose Naltrexone Therapy Improves Active Crohn’s Disease STUDY HIGHLIGHTS What Is Current Knowledge The current medical therapy of Crohn’s disease includes medications that target the immune system or inflammatory modulators. Opioid systems (peptides and receptors) play an integral role in gastrointestinal fluid regulation, pain perception, and inflammation. Many of the current drugs for treatment of Crohn’s disease carry a greater risk of infection from immunosuppression or allergic reactions, and some must be administered parenterally. What Is New Here An opioid antagonist, naltrexone 4.5 mg, administered by mouth once daily significantly improved Crohn’s disease activity index (CDAI) scores and symptoms in subjects with active Crohn’s disease. Quality of life significantly improved with low-dose naltrexone therapy and remained improved after discontinuation of the drug. Naltrexone therapy was well tolerated in Crohn’s disease with minimal side effects. 7 Low-dose naltrexone therapy in multiple sclerosis Agrawal Y.P. The use of low doses of naltrexone for the treatment of multiple sclerosis (MS) enjoys a worldwide following amongst MS patients. There is overwhelming anecdotal evidence, that in low doses naltrexone not only prevents relapses in MS but also reduces the progression of the disease. It is proposed that naltrexone acts by reducing apoptosis of oligodendrocytes. It does this by reducing inducible nitric oxide synthase activity. This results in a decrease in the formation of peroxynitrites, which in turn prevent the inhibition of the glutamate transporters. Thus, the excitatory neurotoxicity of glutamate on neuronal cells and oligodendrocytes via activation of the a-amino-3- hydroxy-5-methyl-isoxazole-4-propionic acid class of glutamate receptor is prevented. It is crucial that the medical community respond to patient needs and investigate this drug in a clinical trial. 8 Antibodies to Neuron-Specific Antigens in Children with Autism: Possible Cross-Reaction with Encephalitogenic Proteins from Milk, Chlamydia pneumoniae and Streptococcus Group A Journal of Neuroimmunology, 129:168-177 2002 A. Vojdani, A.W. Campbell, E. Anyanwu, A. Kashanian, K. Bock, E. Vojdani Infections, Toxic Chemicals and Dietary Peptides Binding to Lymphocyte Receptors and Tissue Enzymes are Major Instigators of Autoimmunity in Autism Int J Immunopathol Pharmacol 16(3):189-199, 2003 A. Vojdani, J.B. Pangborn, E. Vojdani, E.L.Cooper Heat Shock Protein and Gliadin Peptide Promote Development of Peptidase Antibodies in Children with Autism and Patients with Autoimmune Disease Clin Diag Lab Immunol 11(3):515-524, 2004 A. Vojdani, M. Bazargan, E. Vojdani, J. Samadi, A.A. Nourian, N. Eghbalieh, E.L. Cooper Immune Response to Dietary Proteins, Gliadin and Cerebellar Peptides in Children with Autism Nutritional Neuroscience, 7(3):151-161, 2004 Vojdani, T. O’Bryan, J.A. Green, J. McCandless, K.N. Woeller, E. Vojdani, A.A. Nourian, E.L. Cooper Antibodies against Central Nervous System Antigens in Autism: Possible Cross-Reaction with Dietary Proteins and Infectious Agent Antigens. Neuropsychiatric Disorders & Infections, pp 171-186, 2005, S.H. Fatemi (ed), Taylor & Francis Ltd Vojdani, T. O’Bryan, J.A. Green, J. McCandless, K.N. Woeller, E. Vojdani, A.A. Nourian, E.L. Cooper 9 journal of Neuroimmunology Journal of Neuroimmunology (In Press) Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15 A. Vojdani, et al. Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells. At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (p < 0.001). Low NK cell activity in both groups did not correlate with percentage and absolute number of CD16+/CD56+ cells. When the NK “The induction NK cellbased activity by IL-2,CD16 IL-15 and glutathione waswho more +/CD56 + cells, cytotoxic activity wasofexpressed on activity/100 several patients had displayed NK cell activity belowin15aLU exhibited normal celllow activity. after this We correction factor, 45% of 45% the children pronounced subgroup with NK very NKOverall, cell activity. conclude that of with autism still exhibited low NK cell activity, correlating with the intracellular level of glutathione. Finally, we a subgroup of children autism low with NK orcell activity, and IL-2 thatand low cultured lymphocytes of patientswith with low or highsuffers NK cell from activity/cell without glutathione, IL-15. intracellular of glutathione, IL-2 IL-15wasmay responsible.” The induction of levels NK cell activity by IL-2, IL-15 and and glutathione morebe pronounced in a subgroup with very low NK cell activity. We conclude that 45% of a subgroup of children with autism suffers from low NK cell activity, and that low intracellular levels of glutathione, IL-2 and IL-15 may be responsible. 100 90 81% 80 71% 70% 64% 70 56% 60 50% 50 56% 53% 46% 41% 40 30 20 8% 10 0 Controls 1 2 3 4 5 6 7 8 9 10 Figure 2 - % NK cell activity below 15 lytic units in controls and patients with autism Percentage of NK activity below 15 lytic units in controls and patients obtained from 10 cell different clinics with autism obtained from 10 different clinics. Vojdani A. et al., Journal of Neuroimmunology 2008 (In Press) 11 12 Effects of Opioids on the Immune System Schematic representation of the hematopoietic system showing the differentiation pathways sensitive to opioids. from Effects of Opioids on the Immune System – Roy S. and Loh H.H., Neurochemical Research, 21:1375-1386, 1996 13 NALTREXONE High Dose Low Dose d-Opioid Receptor Antagonist d-Opioid Receptor Agonist Inhibition of T, B and NK function IFN-g and IL-2 production Stimulation of T, B and NK function IFN-g and IL-2 production 14 MECHANISM OF ACTION OF LDN LDN Increase in endogenous enkephalin and endorphin Inhibition of proinflammatory cytokines Interaction of the nuclear opioid growth factor receptor Blockade of opiate-R in GI tract Regulation of TReg and production of IL-10 and TGF-b Effect on no. of liquid bowel movements Promotion Of DNA synthesis Enhancement of immune function Improvement in inflammatory reaction Healing of corneal ulcers Healing & repair of mucosal tissue Improvement in Crohn’s disease activity Down regulation of TH-17 15 The Role of Environmental Factors in Gut-Brain Inflammation and Its Possible Inhibition by LDN LDN LDN LDN LDN LDN LDN 16