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

ABSTRACT

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