Targeted depletion of lymphotoxin-α–expressing TH1 and TH17 cells inhibits autoimmune disease
| Autor: | Sinisa Ivelja, Xin Yu, Ganesh Kolumam, Kai H. Barck, Canio J. Refino, Andres Paler-Martinez, Ivan Peng, Jane L. Grogan, Wyne P. Lee, Lauri Diehl, Peter Gribling, Devavani Chatterjea, Allen Nguyen, Eugene Y. Chiang, Judy Young, Mercedesz Balazs, Michelle Francesco, Richard A.D. Carano, Jean Shu, Ron Ferrando |
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| Rok vydání: | 2009 |
| Předmět: |
Inflammation
Autoimmune disease Lymphotoxin alpha medicine.drug_class Interleukin-17 Antibodies Monoclonal Arthritis General Medicine Th1 Cells Biology medicine.disease Monoclonal antibody Arthritis Experimental Lymphocyte Depletion General Biochemistry Genetics and Molecular Biology Autoimmune Diseases Mice Downregulation and upregulation Mice Inbred DBA Immunology medicine biology.protein Animals Antibody Lymphotoxin-alpha |
| Zdroj: | Nature Medicine. 15:766-773 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm.1984 |
| Popis: | Uncontrolled T helper type 1 (T(H)1) and T(H)17 cells are associated with autoimmune responses. We identify surface lymphotoxin-alpha (LT-alpha) as common to T(H)0, T(H)1 and T(H)17 cells and employ a unique strategy to target these subsets using a depleting monoclonal antibody (mAb) directed to surface LT-alpha. Depleting LT-alpha-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-alpha-specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon-gamma and tumor necrosis factor-alpha (TNF-alpha), whereas decoy lymphotoxin-beta receptor (LT-betaR) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fcgamma 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-1beta and TNF-alpha within joints. These data indicate that depleting LT-alpha-expressing lymphocytes with LT-alpha-specific mAb may be beneficial in the treatment of autoimmune disease. |
| Databáze: | OpenAIRE |
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