Abstract
Purpose: :
1,25–Dihydroxyvitamin D3 (calcitriol), one of Vitamin D receptor (VDR) agonists, and its synthetic analogue have been shown beneficial effects on autoimmune diseases, but the role in autoimmune retinal diseases is unknown. This study aims to identify the role of VDR agonists in treatment of experimental autoimmune uveoretinitis (EAU).
Methods: :
EAU–susceptible B10.RIII mice were immunized with an uveitogenic regimen of 8 µg IRBP in CFA and treated orally with calcitriol or with its two synthetic analogs, BXL–35 or BXL–38, before or after EAU induction. EAU development was examined by funduscopy and confirmed on day 21 post–immunization by histopathology on eyes. On the same day, the antigen–driven lymph node proliferation from treated mice was assayed by tritiated thymidine incorporation and the cytokines from the proliferating cultures were assayed by ELISA.
Results: :
Calcitriol at 0.5 µg/kg and BXL–35 at 10 µg/kg can prevent EAU, when administered from day –5 to 21, whereas no protective effect was induced by BXL–38. In addition, BXL–35 but not calcitriol could inhibit EAU development when treatment was started 7 days after immunization. Protected mice had reduced antigen–specific DTH responses to IRBP. In vitro antigen–specific responses indicated that calcitriol and BXL–35 had little effect on T cell proliferation, but rather appeared to affect effector function by altering the cytokine and chemokine profile. Namely, treatment with VDR agonist before immunization decreased both IFN–gamma and IL–17 production by LN, whereas treatment with BXL–35 after immunization inhibited IL–17 but no longer affected IFN–g production. Consistent with disease amelioration, VDR agonists inhibited Ag driven chemokine release, such as MIP–1α, RANTES and TARC.
Conclusions: :
VDR agonists can prevent and treat EAU, most likely by altering the proinflammatory cytokine and chemokine profile. Inhibition of IL–17, MIP–1α, RANTES and TARC, but not of IFN–γ, was associated with protection from disease.
Keywords: autoimmune disease • uvea • retinitis