The complement inhibitor FUT-175 suppresses T cell autoreactivity in experimental autoimmune encephalomyelitis.
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-gamma 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-gamma- 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.
Li
Qing
Q
Assistant Professor, Institute of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Road, Room 306, Cleveland, OH 44106, USA.
Nacion
Kristine
K
Bu
Hong
H
Lin
Feng
F
D000818:Animals; D001550:Benzamidines; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D006146:Guanidines / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D001550:Benzamidines; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D050577:Complement C3-C5 Convertases; C032855:nafamostat