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

被引：146

作者：

Chiang, Eugene Y. ^{[1
]}

Kolumam, Ganesh A. ^{[1
]}

Yu, Xin ^{[1
]}

Francesco, Michelle ^{[1
]}

Ivelja, Sinisa ^{[1
]}

Peng, Ivan ^{[1
]}

Gribling, Peter ^{[1
]}

Shu, Jean ^{[1
]}

Lee, Wyne P. ^{[1
]}

Refino, Canio J. ^{[1
]}

Balazs, Mercedesz ^{[1
]}

Paler-Martinez, Andres ^{[1
]}

Nguyen, Allen ^{[2
]}

Young, Judy ^{[2
]}

Barck, Kai H. ^{[3
]}

Carano, Richard A. D. ^{[3
]}

Ferrando, Ron ^{[4
]}

Diehl, Lauri ^{[4
]}

Chatterjea, Devavani ^{[1
]}

Grogan, Jane L. ^{[1
]}

机构：

[1] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Assay & Automat Technol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Tumor Biol & Angiogenesis, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA

来源：

NATURE MEDICINE | 2009年 / 15卷 / 07期

关键词：

TUMOR-NECROSIS-FACTOR; COLLAGEN-INDUCED ARTHRITIS; T-CELL; B-CELL; SURFACE LYMPHOTOXIN; IL-17-DEFICIENT MICE; HUMORAL RESPONSES; TH17; CELLS; INFLAMMATION; IL-17;

D O I：

10.1038/nm.1984

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-beta R) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fc gamma 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 beta 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.

引用

页码：766 / U10

页数：9

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