The HLA-B*5101 molecule-binding capacity to antigens used in animal models of Behçet's disease: a bioinformatics study.

BACKGROUND: The human lymphocyte antigen (HLA) molecule B*5101 is a functioning receptor of the immune system and is generally accepted as a genetic marker for Behçet disease (BD), a multi-organ, chronic inflammatory disorder. The role of the HLA-B*5101 in the pathogenesis of BD is elusive. The assumption that HLA-B*5101 has an active role in BD is suggestive, but no antigen has yet been identified. OBJECTIVES: To evaluate the potential binding capacity of various antigens to the HLA-B*5101 molecule. METHODS: Using bioinformatics programs, we studied the binding capacity of HLA-B*5101 and its corresponding rat molecule RT.A1 to the following antigens: heatshock protein-60 (HSP60), major histocompatibility complex class I chain-related gene A (MICA), retinal S-antigen (S-Ag), HLA-B27 molecule and its peptide (PD) and tropomyosin (TPM), all of which serve as antigens in animal models corresponding to BD. RESULTS: In each protein including the B*5101 molecule itself, the computerized programs revealed several short sequences with potential high binding capacity to HLA-B*5101 with the exception of B-27PD. The rat MHC RT1. Al. had no binding capacity to S-Ag. CONCLUSIONS: The evaluated proteins have the potential to bind to and to serve as potential antigens to the HLA-B*5101 and the rat MHC RT1.Al. molecules. The pathogenicity of these suggested short peptides should be evaluated in animal models of BD.

Immunomodulatory effect of sertraline in a rat model of rheumatoid arthritis.

OBJECTIVE: Previous studies suggest that selective serotonin reuptake inhibitors (SSRIs) modulate immune system functionality. SSRIs are the preferred treatment for major depressive disorder (MDD). A high rate of MDD is observed in rheumatoid arthritis (RA) patients. The aim of this study was to evaluate immunological effects of SSRIs in a rat model of RA. METHODS: Adjuvant arthritis was induced in 8-week-old Lewis rats; in the first set of experiments following the induction, 15.3 or 30.6 mg/kg of sertraline was daily injected into the ankle joint of the left rear leg. Clinical disease activity was evaluated and the findings compared with the 3 untreated legs and with control groups given methotrexate (MTX) or vehicle only at the same site. In a second set of experiments, the effect of 5, 25 and 50 mg/kg daily oral sertraline was evaluated in the same rat model. Splenocyte viability and inflammatory mediators were evaluated. RESULTS: The sertraline-treated rats showed a significant reduction in clinical arthritis compared to controls, at all doses given, accompanied by a significant increase in interleukin 10 and a decrease in tumor necrosis factor-α levels and cycloxygenase-2 production, without lymphotoxicity. There was no significant difference from MTX, the first-line treatment for RA patients. Oral sertraline had a significant anti-inflammatory effect at all doses. There was no treatment × time effect. CONCLUSION: The beneficial effects of sertraline in this rat model of arthritis have clinical implications for its use in humans. Large-scale clinical efficacy trials are needed.

The influence of DHEA pretreatment on prepulse inhibition and the HPA-axis stress response in rat offspring exposed prenatally to polyriboinosinic-polyribocytidylic-acid (PIC).

Prenatal exposure to maternal infection may be associated with the development of neurodevelopmental disorders as well as increased susceptibility to the development of schizophrenia. Prenatal administration of polyriboinosinic-polyribocytidilic-acid, mimicking RNA virus exposure, has been shown to induce schizophrenia-like behavioral, neurochemical and neuorophysiological abnormalities in rodent offspring. In the present study PIC prenatal administration at gestation day 15 was associated with alterations in the acoustic-startle-response/prepulse-inhibition [ASR/PPI] and the HPA-axis stress response in rat offspring on day 90. We show that pretreatment with dehydroepiandrosterone (DHEA) reverses PIC-related ASR/PPI disruption in female rats and normalizes HPA-axis stress response in a united group of male and female rats. Further research in both animal and human studies is recommended in order to confirm these preliminary findings and their application to the understanding and management of schizophrenia and related conditions.

Evidence for an inhibitory immunomodulatory effect of selected antidepressants on rat splenocytes: possible relevance to depression and hyperactive-immune disorders.

Antidepressants have been found to possess antiproliferative effect. In the immune system depression may activate pro-inflammatory cytokines. Therefore, the aim of this study was to assess the immunomodulatory activity of antidepressants in naïve rat. Rat splenocytes were activated with con A and treated with paroxetine, sertraline or clomipramine ex vivo. We found that the antidepressants inhibit cell viability and proliferation at IC50 of 5-8 microM of mitogen-stimulated rat splenocytes. This inhibitory effect was accompanied by cell cycle arrest and increase in apoptotic events as assayed by FACS. Moreover, antidepressants decrease the secretion of the TH1 factor--TNFalpha. In addition, the antidepressants reduced the expression of the enzyme cyclooxygenase2 which is involved in inflammation. On the cellular level we show the up-regulation of MAPK death signaling pathway and suppression of the anti-apoptotic factor--Bcl-2. These findings reveal the immunomodulatory effect of the selected antidepressants. These data suggest a novel use of antidepressants or their derivatives.

Immunomodulatory effect of selective serotonin reuptake inhibitors (SSRIs) on human T lymphocyte function and gene expression.

Antidepressants have an antiproliferative effect in some cell lines. Depression may be associated with activation of some pro-inflammatory cytokines. Therefore, we evaluated the ex-vivo immunomodulatory effect of selective serotonin reuptake inhibitors (SSRIs) in T cells. We found that the SSRIs, paroxetine and sertraline decreased T-cell viability with IC50 around 10 microM. The inhibition obtained with exposure to the SSRIs was more pronounced than that achieved with dexamethasone. Moreover, these SSRIs inhibit the secretion of the TH1 factor-tumor necrosis factor(TNF)alpha from the cells. On the molecular level, the SSRIs suppressed signal transducer and activator of transcription 3 (Stat3) and cyclooxygenase(Cox)2 protein expression. The inhibitory effects were accompanied by alterations in gene expression as assessed in the gene array. These findings reveal an immunomodulatory effect of the SSRIs paroxetine and sertraline in human T cells. The clinical implications of our findings merit further investigation.

The PI3K-NF-kappaB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant-induced arthritis.

The anti-inflammatory effect of adenosine was previously found to be mediated via activation of the A3 adenosine receptor (A3AR). The aim of the present study was to decipher the molecular mechanism involved with the inhibitory effect of IB-MECA, an A3AR agonist, on adjuvant-induced arthritis. The adjuvant-induced arthritis rats responded to IB-MECA treatment with a decrease in the clinical score and the pathological score of the disease. The response to IB-MECA was neutralized by the antagonist MRS 1220, confirming that the efficacy of the synthetic agonist was A3AR mediated. The A3AR protein expression level was highly expressed in the synovia, in the peripheral blood mononuclear cells and in the drain lymph node (DLN) tissues of adjuvant-induced arthritis rats in comparison with naïve animals. Downregulation of A3AR expression was noted upon treatment with IB-MECA. Analysis of synovia and DLN protein extracts revealed a decreased expression level of PI3K, PKB/Akt, IKK, NF-kappaB and tumor necrosis factor alpha, known to affect survival and apoptosis of inflammatory cells, whereas the caspase-3 level was upregulated.Taken together, high A3AR expression is found in the synovia, in the immune cells in the DLN and in peripheral blood mononuclear cells. IB-MECA, an orally bioavailable molecule, activates the A3AR, inducing receptor downregulation and the initiation of a molecular mechanism that involves de-regulation of the PI3K-NF-kappaB signaling pathway. As a result, a potent anti-inflammatory effect manifested in the improvement of the disease clinical score and pathological score occurs. The finding that the A3AR expression level in the peripheral blood mononuclear cells and in the DLN reflects the receptor status in the remote inflammatory site suggests use of the A3AR as a follow-up biomarker.

Antiinflammatory effect of A3 adenosine receptor agonists in murine autoimmune arthritis models.

OBJECTIVE: CF101, an A3 adenosine receptor (A3AR) agonist, is a small orally bioavailable molecule known to suppress in vitro the production of tumor necrosis factor-alpha (TNF-alpha). We evaluated its therapeutic potential and antiinflammatory effects in 3 murine models of adjuvant induced arthritis (AIA). METHODS: The antiinflammatory effect of CF101 was examined in rat AIA, in mouse collagen induced arthritis, and in tropomyosin induced arthritis. The clinical effect of another A3AR agonist, Cl-IB-MECA, was examined in rat AIA. The effect of low dose (10 or 100 mg/kg/day) A3AR agonists administered orally once daily on arthritis severity was assessed clinically and histologically. The effect of CF101 on the protein expression level of TNF-alpha in the synovial tissue, draining lymph nodes, and spleen cells was determined by Western blot. RESULTS: CF101 and Cl-IB-MECA markedly ameliorated the clinical and histological features of arthritis in the 3 models when administered orally at a low dose of 10 mg/kg body weight in the 3 autoimmune arthritis models. The lower dose of 10 mg/kg of either CF101 or Cl-IB-MECA had better antiinflammatory effect than the higher 100 mg/kg dose. Decreased expression of TNF-alpha was noted in protein extracts of synovia, draining lymph nodes, and spleen tissues. CONCLUSION: The results provide evidence that A3AR agonists exert significant antirheumatic effects in different autoimmune arthritis models by suppression of TNF-alpha production. The beneficial activity of the drugs at the low dose demonstrates that the effect is A3AR mediated.

Lactobacillus GG bacteria ameliorate arthritis in Lewis rats.

Probiotic bacteria have beneficial effects in infectious and inflammatory diseases, principally in bowel disorders. In the case of chronic progressive autoimmune arthritides, a major goal of treatment is to reduce inflammation. We hypothesized that probiotic bacteria would ameliorate inflammation found in arthritis models. To assess this effect, Lewis rats were injected with 50 microg bovine alpha-tropomyosin (TRM) or complete Freund's adjuvant (CFA) to induce tropomyosin arthritis (TA) or adjuvant arthritis (AA), respectively. In both models, the rats were divided into 6 groups and fed 0.5 mL/d of the following suspensions: 1) heat-killed Lactobacillus GG (LGG) bacteria; 2) live LGG, both 10(11) colony-forming units (cfu)/L; 3) sterilized milk; 4) plain yogurt; 5) yogurt containing 10(11) cfu/L LGG; or 6) sterilized water. In the disease-prevention experiments, feeding started 1 wk before or after disease induction. In the therapeutic experiments, feeding was initiated at the onset of clinical arthritis. In all experiments, there were significant interactions between time and treatment (P < 0.001), except for milk, which had no effect in the therapeutic experiment. Histologically, rats fed yogurt containing LGG had a milder inflammation in all experiments (P < 0.05), whereas rats fed plain yogurt exhibited a moderate inflammatory score only in the prevention experiments. Anti-TRM antibody titers were not affected by any of the treatments in any of the experiments. Ingestion of live or heat-killed human LGG had a clinically beneficial effect on experimental arthritis. Our observation of the remarkable preventive and curative effect on arthritis using commercial yogurts containing lactobacilli, especially LGG, suggests the need for investigation of these agents in arthritic patients.