Targeted depletion of lymphotoxin-α–expressing TH1 and TH17 cells inhibits autoimmune disease

EY Chiang, GA Kolumam, X Yu, M Francesco… - Nature medicine, 2009 - nature.com
EY Chiang, GA Kolumam, X Yu, M Francesco, S Ivelja, I Peng, P Gribling, J Shu, WP Lee…
Nature medicine, 2009nature.com
Uncontrolled T helper type 1 (TH1) and TH17 cells are associated with autoimmune
responses. We identify surface lymphotoxin-α (LT-α) as common to TH0, TH1 and TH17
cells and employ a unique strategy to target these subsets using a depleting monoclonal
antibody (mAb) directed to surface LT-α. Depleting LT-α–specific mAb inhibited T cell–
mediated models of delayed-type hypersensitivity and experimental autoimmune
encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic …
Abstract
Uncontrolled T helper type 1 (TH1) and TH17 cells are associated with autoimmune responses. We identify surface lymphotoxin-α (LT-α) as common to TH0, TH1 and TH17 cells and employ a unique strategy to target these subsets using a depleting monoclonal antibody (mAb) directed to surface LT-α. Depleting LT-α–specific mAb inhibited T cell–mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of LT-α–specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon-γ and tumor necrosis factor-α (TNF-α), whereas decoy lymphotoxin-β receptor (LT-βR) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fcγ receptor binding and antibody-dependent cellular cytotoxicity activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6, IL-1β and TNF-α within joints. These data indicate that depleting LT-α–expressing lymphocytes with LT-α–specific mAb may be beneficial in the treatment of autoimmune disease.
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