Targeted depletion of lymphotoxin-alpha-expressing Th1 and Th17 cells inhibits autoimmune disease (48.22)

Abstract

Abstract Aberrant autoimmune responses are often underpinned by dysregulated and uncontrolled CD4+ T helper (Th) cell subsets Th1 and Th17. We identify surface lymphotoxin-alpha (LTa) as common to Th1 and Th17 cells and employ a novel strategy to target these subsets using a depleting monoclonal antibody directed to surface LTa. A depleting anti-LTa mAb inhibited T cell-mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of anti-LTa; inhibited disease, resulting in immunoablation of T cells expressing IL-17, IFN-g; and TNF-a, whereas a decoy LTbR fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of FcgR binding and ADCC activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6, IL-1b and TNF-a within joints. These data indicate that depleting Th1 and Th17 with anti-LTa mAb may be beneficial in the treatment of autoimmune disease.