Immune mechanisms in the pathogenesis of idiopathic anterior uveitis.

Abstract

Idiopathic anterior uveitis (IAU) is a blinding disease characterized by inflammation of the iris and the ciliary body (CB) of the eye. IAU is treated symptomatically only using non-specific therapies such as steroid and immunosuppressive agents. These treatment modalities do not address the underlying mechanisms and are associated with adverse side effects. Experimental autoimmune anterior uveitis (EAAU) is a clinically relevant animal model of human IAU. In the current study we used EAAU animal model to investigate underlying mechanisms involved in regulation of inflammation in IAU. EAAU was induced in Lewis rats by immunization with melanin associated antigen (MAA). We observed that Th17 cells (IL-17 producing CD4⁺ cells and CD4⁺RORγt⁺ cells) accumulated in rat eyes at the onset and the peak of the disease. During the resolution of EAAU, Th17 cells declined while CD4⁺CD25⁺FoxP3⁺ T regulatory (Tregs) cells accumulated in the eyes. Administration of recombinant TGF-β2 during the early stages of EAAU prevented the induction of uveitis by inhibiting CD4⁺T proliferation and increasing the number of CD4⁺CD25⁺FoxP3⁺ Tregs. Severity of active (on-going) EAAU was reduced only for the time of active treatment with TGF-β2. Adoptive transfer of CD4⁺CD25⁺ T regulatory cells after the onset of EAAU resulted in sharp decline in disease activity and early resolution of EAAU. In conclusion, our results demonstrate that TGF-β2 plays a pivotal role in regulation of intraocular inflammation in EAAU. Collectively, these results raise the possibility that human IAU can be treated perhaps by enhancing the generation of Tregs by TGF-β2. Additionally, Treg cell therapy is potentially a promising strategy in the treatment of established human IAU.