Article abstract
Nature Medicine 15, 766 - 773 (2009)
Published online: 28 June 2009 | doi:10.1038/nm.1984
Targeted depletion of lymphotoxin-
–expressing TH1 and TH17 cells inhibits autoimmune disease
Eugene Y Chiang1,5, Ganesh A Kolumam1,5, Xin Yu1, Michelle Francesco1, Sinisa Ivelja1, Ivan Peng1, Peter Gribling1, Jean Shu1, Wyne P Lee1, Canio J Refino1, Mercedesz Balazs1, Andres Paler-Martinez1, Allen Nguyen2, Judy Young2, Kai H Barck3, Richard A D Carano3, Ron Ferrando4, Lauri Diehl4, Devavani Chatterjea1 & Jane L Grogan1
Abstract
Uncontrolled T helper type 1 (TH1) and TH17 cells are associated with autoimmune responses. We identify surface lymphotoxin-
(LT-) 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-. Depleting LT-–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-–specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon-
and tumor necrosis factor- (TNF-), whereas decoy lymphotoxin-
receptor (LT-R) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fc 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-1 and TNF- within joints. These data indicate that depleting LT-–expressing lymphocytes with LT-–specific mAb may be beneficial in the treatment of autoimmune disease.
- Departments of Immunology, South San Francisco, California, USA.
- Assay and Automation Technology, South San Francisco, California, USA.
- Tumor Biology and Angiogenesis, South San Francisco, California, USA.
- Pathology, Genentech, Inc., South San Francisco, California, USA.
- These authors contributed equally to this work.
Correspondence to: Jane L Grogan1 e-mail: jgrogan@gene.com
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