title: Targeted depletion of lymphotoxin-alpha-expressing TH1 and TH17 cells inhibits autoimmune disease.
abstract: 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.
authors: Department of Immunology, South San Francisco, California, USA.
authors: Eugene Y
authors: EY
authors: Chiang
authors: Ganesh A
authors: GA
authors: Kolumam
authors: Xin
authors: X
authors: Yu
authors: Michelle
authors: M
authors: Francesco
authors: Sinisa
authors: S
authors: Ivelja
authors: Ivan
authors: I
authors: Peng
authors: Peter
authors: P
authors: Gribling
authors: Jean
authors: J
authors: Shu
authors: Wyne P
authors: WP
authors: Lee
authors: Canio J
authors: CJ
authors: Refino
authors: Mercedesz
authors: M
authors: Balazs
authors: Andres
authors: A
authors: Paler-Martinez
authors: Allen
authors: A
authors: Nguyen
authors: Judy
authors: J
authors: Young
authors: Kai H
authors: KH
authors: Barck
authors: Richard A D
authors: RA
authors: Carano
authors: Ron
authors: R
authors: Ferrando
authors: Lauri
authors: L
authors: Diehl
authors: Devavani
authors: D
authors: Chatterjea
authors: Jane L
authors: JL
authors: Grogan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000628:therapy; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D007249:Inflammation / Q000209:etiology; D020381:Interleukin-17 / Q000502:physiology*; D008212:Lymphocyte Depletion; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors*; D051379:Mice; D008811:Mice, Inbred DBA; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D008233:Lymphotoxin-alpha