Targeted depletion of lymphotoxin-alpha-expressing TH1 and TH17 cells inhibits autoimmune disease.
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.
Chiang
Eugene Y
EY
Department of Immunology, South San Francisco, California, USA.
Kolumam
Ganesh A
GA
Yu
Xin
X
Francesco
Michelle
M
Ivelja
Sinisa
S
Peng
Ivan
I
Gribling
Peter
P
Shu
Jean
J
Lee
Wyne P
WP
Refino
Canio J
CJ
Balazs
Mercedesz
M
Paler-Martinez
Andres
A
Nguyen
Allen
A
Young
Judy
J
Barck
Kai H
KH
Carano
Richard A D
RA
Ferrando
Ron
R
Diehl
Lauri
L
Chatterjea
Devavani
D
Grogan
Jane L
JL
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*
D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D008233:Lymphotoxin-alpha