Effect of fasudil on experimental autoimmune neuritis and its mechanisms of action

This study aimed to investigate the therapeutic effect of fasudil on treating experimental autoimmune neuritis (EAN). Twenty-four EAN mice were randomly assigned to fasudil treatment (Fasudil group) or saline treatment (EAN model group) for 28 days. Clinical symptom score was evaluated every other day; inflammatory cell infiltration, demyelination, anti-myelin basic protein (MBP), inflammatory cytokines, inducible nitric oxide synthase (iNOS), and arginase-1 were detected in sciatic nerves at day 28. Th1, Th2, Th17, and Tregs proportions in splenocytes were detected at day 28. Clinical symptom score was found to be attenuated in the Fasudil group compared to the EAN model group from day 12 to day 28. Sciatic nerve inflammatory cell counts by HE staining and demyelination by luxol fast blue staining were both reduced, while MBP was increased in the Fasudil group compared to the EAN model group at day 28. Interferon γ (IFN-γ) and interleukin (IL)-17 were reduced, while IL-4 and IL-10 were elevated in the Fasudil group at day 28. Sciatic nerve M1 macrophages marker iNOS was decreased while M2 macrophages marker arginase-1 was increased in the Fasudil group at day 28. CD4+IFN-γ+ (Th1) and CD4+IL-17+ (Th17) cell proportions were both decreased, CD4+IL-4+ (Th2) cell proportion was similar, while CD25+FOXP3+ (Treg) cell proportion in splenocytes was increased in the Fasudil group. In summary, fasudil presented a good therapeutic effect for treating EAN by attenuating Th1/Th17 cells and promoting Tregs activation as well as M2 macrophages polarization.

Adiponectin inhibits oxidization-induced differentiation of T helper cells through inhibiting costimulatory CD40 and CD80

Adiponectin is a multifunctional adipokine that has several oligomeric forms in the blood stream, which broadly regulates innate and acquired immunity. Therefore, in this study, we aimed to observe the differentiation of T helper (Th) cells and expression of costimulatory signaling molecules affected by adiponectin. The mRNA and protein expression levels of adiponectin and its receptors in oxidized low density lipoprotein cholesterol-treated endothelial cells were assayed by real time PCR and immunofluorescence. The endothelial cells were then treated with adiponectin with or without adipoR1 or adipoR2 siRNA and co-cultured with T lymphocytes. The distribution of Th1, Th2 and Th17 subsets were assayed by flow cytometry. The effects of adiponectin on costimulatory signaling molecules HLA-DR, CD80, CD86 and CD 40 was also assayed by flow cytometry. The results showed that endothelial cells expressed adiponectin and its receptor adipoR1 and adipoR2, but not T-cadherin. Adiponectin suppressed Th1 and Th17 differentiation through adipoR1 receptor, contributed to the inhibition of CD80 and CD40, and inhibited differentiation of Th1 and Th17 by inhibiting antigen presenting action.

Effect of thymosin alpha-1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro

Thymosin alpha 1 (Tα1) has been shown to have beneficial effects on numerous immune system parameters, but little is known about the effects of Tα1 on patients with gastric carcinoma. The objective of this study was to determine the effect of Tα1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro, and to evaluate its efficacy as an immunoregulatory factor in patients with gastric carcinoma. We compared the effect of Tα1 on the frequency of CD4+ and CD8+ T cells, especially the CD4+CD25+Foxp3+ Tregs in peripheral blood mononuclear cells (PBMCs) from gastric carcinoma patients (N = 35) and healthy donors (N = 22). We also analyzed the changes in the proliferation of PBMCs in response to treatment with Tα1, and examined the production of Th1, Th2, and Th17 cytokines by PBMCs and tumor-infiltrating lymphocytes. The treatment of PBMCs from gastric cancer patients, with Tα1 (50 µg/mL) alone increased the percentage of CD4+CD25+Foxp3+ (suppressive antitumor-specific Tregs) from 1.68 ± 0.697 to 2.19 ± 0.795 percent (P < 0.05). Our results indicate that Tα1 increases the percentage of Tregs and IL-1β, TNF-α, and IL-6 in vitro.

Therapeutic effects of all-trans retinoic acid on experimental autoimmune encephalomyelitis and its role in T-helper lymphocyte responses

Recent studies have demonstrated an essential role for IL-17 in the pathogenesis of experimental autoimmune encephalomyelitis [EAE]. Furthermore, it has been shown that FoxP3+Treg cells play an important role in the suppression of auto inflammatory reactions. Although, previous studies have determined the immunomodulatory potentials of all-trans-retinoic acid [ATRA], but these immunomodulations have been mostly justified by alteration in Thl/Th2 cytokines. The present study was carried out to investigate the therapeutic effects of ATRA on EAE and its effects on T-helper cells responses. EAE was induced by MOG[35-55] peptide and complete Freund's adjuvant in female C57BL/6 mice. The mice were allocated to two therapeutic groups [n=7 per group]. Treatment with ATRA [500 microg/mouse; every other day] was initiated in treatment group on day 12 when they developed a disability score. EAE controls received vehicle alone with the same schedule. Signs of disease were recorded daily until day 33 when the mice were sacrificed. Splenocytes were tested for proliferation by MTT test, cytokine production by ELISA and FoxP3[+] reg cell frequency by flowcytometry. ATRA significantly reduced the clinical signs of established EAE. Aside from decreasing lymphocytic proliferation [P<0.05], ATRA significantly inhibited the production of pro-inflammatory IL-17 [P<0.005] as well as IFN-gamma [P<0.0005] upon antigen-specific restimulation of splenocytes. FoxP3+Treg cell frequency and IL-10 levels were not altered significantly. However, IFN-gamma to IL-10 and IL-17 to IL-10 ratios decreased significantly [P<0.0005]. Parallel to reducing autoreactive lymphocyte proliferation and cytokine production in favor of pro-inflammatory cytokines, all-trans-retinoic acid ameliorated established experimental autoimmune encephalomyelitis

Effect of lecithin with vitamin-B complex and tocopheryl acetate on long-term effect of ethanol induced immunomodulatory activities.

The alcoholic liver disease usually causes overall immunological alterations which might be attributed to hepatic disease, to ethanol action, and/or to malnourishment. In the present study, efficacy of lecithin with vitamin-B complex to treat ethanol induced immunomodulatory activity was compared with the effect of lecithin alone and tocopheryl acetate (vitamin E). Ethanol (1.6 g/kg body wt/day for 12 weeks) exposure increased thiobarbituric acid reactive substance (TBARS) level, while decreased superoxide dismutase (SOD) activity and reduced glutathione (GSH) content in whole blood hemolysate of 8-10 week-old male BALB/c mice (weighing 20-30 g). The activities of transaminase (AST and ALT) enzymes, interleukin (IL)-10 and gamma interferon (IFN-gamma) elevated, while IL-2 and IL-4 reduced in mice serum due to ethanol exposure. These suggested that oxidative stress and immunomodulatory activities were interdependent and associated with ethanol induced liver damage. Lecithin treatment significantly reduced AST (32.44%), ALT (32.09%), IL-10 (25.63%) activities and TBARS content (12.76%) compared to ethanol treated group. However, lecithin with vitamin-B complex treatment, significantly reduced AST (62.83%); ALT (61.96%); IL-10 (35.88%); IFN-gamma (22.55%) activities and TBARS content (31.58%), while significantly elevated GSH content (36.49%) and SOD activity (61.21%). Tocopheryl acetate treatment significantly reduced AST (62.83%); ALT (61.54%); IL-10 (36.35%): IFN-gamma (23.28%) activities and TBARS content (35.84%). while significantly elevated GSH content (28.76%) and SOD activity (62.42%) compared to ethanol treated group. These findings persuasively argued that lecithin with vitamin-B complex was a new promising therapeutic approach in controlling ethanol induced immunomodulatory activities involving liver damage processes. Prevention of oxidative stress with correction of nutritional deficiency caused alteration in the ethanol-induced immunomodulatory activities and associated liver diseases.

Role of calcium in induction of dengue virus-specific helper T cells.

Dengue type 2 virus (DV) induces the generation of T helper cells (TH) in the mouse spleen. These TH on adoptive transfer to DV primed syngeneic mice enhance the clonal expansion of antigen-specific antibody plaque forming cells. The present study was undertaken to investigate the role of M phi and Ca2+ in the induction of DV-specific TH. The results show that M phi are obligatory for the induction of DV-specific TH. It was observed that DV antigen stimulate the influx of calcium ion (Ca2+) into T cells as shown by radiolabelled (45Ca) and the influx of Ca2+ increases with time of incubation, reaching a maximum level after 1 hr of incubation. The proliferation of T cells was found to be dependent on presence of Ca2+ as it was inhibited by Ca channel blocking drugs and in the absence of Ca in the medium. Thus showing that Ca2+ plays an important role in the induction of DV-specific TH cells.

T-cell subpopulations in tuberculosis and the effects of rifampicin.

T-cell subpopulations were evaluated by several recent methods in 38 tuberculosis patients (24 active and 10 quiescent cases of pulmonary tuberculosis; two of miliary and two of active extra-pulmonary tuberculosis) before and during rifampicin (RMP) treatment. There was a significant reduction in the total number of T cells (E-RFC and OKT3+ cells) and of helper T cells (OKT4+) coinciding with an increase in the number of suppressor T cells when the 38 tuberculosis patients were compared with 21 healthy control subjects. When the changes of T-cell subpopulations in groups of subjects and patients with different clinical forms of the disease were analysed, these changes could be clearly shown with both sets of assays (receptor assays and monoclonal antibody assays) among those with the active pulmonary form of tuberculosis while similar changes could be demonstrated only by one or the other assay among those with the other forms of the disease. The effects of one month of RMP treatment on these parameters were much more obvious among the clinically active patients than the quiescent patients, i.e. a recovery of total T cells from a low pre-treatment to a near normal level accompanied by a significant reduction in the number of suppressor cells (OKT8+). In fact, among quiescent patients the number of suppressor cells (as TG) appeared to rise further with RMP treatment.