Published online before print July 16, 2009

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(American Journal of Pathology. 2009;175:661-667.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081093

The Complement Inhibitor FUT-175 Suppresses T Cell Autoreactivity in Experimental Autoimmune Encephalomyelitis

Qing Li^*, Kristine Nacion^*, Hong Bu and Feng Lin^*

From the Institute of Pathology,^* Case Western Reserve University, Cleveland, Ohio; and the Department of Pathology, Sichuan University, Chengdu, China

Several recent studies have shown that interacting antigen presenting cells and/or T cells produced complement activation products C5a and C3a, are integrally involved in T-cell activation, and promote the generation of myelin oligodendrocyte glycoprotein (MOG_35–55)-specific interferon- and interleukin-17-producing T cells in experimental autoimmune encephalomyelitis, a rodent model of multiple sclerosis. In this study, we tested whether FUT-175, a clinical pharmaceutical that has been shown to inhibit the formation of C3/C5 convertases, can attenuate myelin-specific T-cell responses, as well as disease severity in experimental autoimmune encephalomyelitis. In vitro, FUT-175 inhibited local C5a/C3a production by antigen presenting cell–T-cell complexes and attenuated MOG_35–55-specific Th1 and Th17 responses with little nonspecific cytotoxicity. In vivo administration of FUT-175 delayed experimental autoimmune encephalomyelitis disease onset, lowered clinical scores, decreased central nervous system inflammation, and reduced demyelination. The FUT-175-treated mice exhibited decreased numbers of MOG_35–55-specific interferon-- and interleukin-17-producing T cells. In addition, results from the FUT-175 treatment of naive recipients of adoptively transferred splenocytes from MOG_35–55-immunized mice suggested that the effect of FUT-175 was on MOG-specific cellular responses and not on anti-MOG antibodies. These results argue that complement regulators, which inhibit C5a/C3a production, may have therapeutic efficacy in multiple sclerosis and in other clinical conditions in which T cells drive disease pathogenesis.

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