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James T. Rosenbaum, Xiumei Wu, Ji Duan, Zili Zhang; Low Dose Rapamycin Exacerbates Autoimmune Experimental Uveitis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4261.
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© ARVO (1962-2015); The Authors (2016-present)
Rapamycin, a potent immune modulator, is used to treat transplant rejection and some autoimmune diseases. Uveitis is a potentially severe inflammatory eye disease, and a clinical trial of treating uveitis with rapamycin is underway. Unexpectedly, recent research has demonstrated that low dose rapamycin enhances the memory T cell population and function. Thus in this study, we sought to determine the effect of low dose rapamycin on the ocular immune response in the setting of uveitis.
B10.RIII mice were immunized to induce experimental autoimmune uveitis (EAU). Ocular inflammation of control and rapamycin-treated mice was compared based on histological change. ELISPOT and T cell proliferation assays were performed to assess splenocyte response to ocular antigen. In addition, we examined the effect of rapamycin on activation-induced cell death (AICD) using the MitoCapture assay and Annexin V staining.
Administration of low dose rapamycin exacerbated EAU, whereas treating mice with high dose rapamycin attenuated ocular inflammation. The progression of EAU by low dose rapamycin coincided with the increased frequency of antigen-reactive lymphocytes. Lastly, fewer rapamycin-treated T cells underwent AICD, which might contribute to exaggerated ocular inflammation and the uveitogenic immune response.
These data reveal a paradoxical role for rapamycin in uveitis in a dose-dependent manner. This study has a potentially important clinical implication as rapamycin might cause unwanted consequences due to different dosing and altered pharmacokinetics. Thus, more research is needed to further define the mechanism by which low dose rapamycin augments the immune response.
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