In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation.
Thymic stromal lymphopoietin (TSLP) potently induces deregulation of Th2 responses, a hallmark feature of allergic inflammatory diseases such as asthma, atopic dermatitis, and allergic rhinitis. However, direct downstream in vivo mediators in the TSLP-induced atopic immune cascade have not been identified. In our current study, we have shown that OX40 ligand (OX40L) is a critical in vivo mediator of TSLP-mediated Th2 responses. Treating mice with OX40L-blocking antibodies substantially inhibited immune responses induced by TSLP in the lung and skin, including Th2 inflammatory cell infiltration, cytokine secretion, and IgE production. OX40L-blocking antibodies also inhibited antigen-driven Th2 inflammation in mouse and nonhuman primate models of asthma. This treatment resulted in both blockade of the OX40-OX40L receptor-ligand interaction and depletion of OX40L-positive cells. The use of a blocking, OX40L-specific mAb thus presents a promising strategy for the treatment of allergic diseases associated with pathologic Th2 immune responses.
Department of Immunology, Genentech Inc., South San Francisco, California 94080, USA.
Dhaya
D
Seshasayee
Wyne P
WP
Lee
Meijuan
M
Zhou
Jean
J
Shu
Eric
E
Suto
Juan
J
Zhang
Laurie
L
Diehl
Cary D
CD
Austin
Y Gloria
YG
Meng
Martha
M
Tan
Sherron L
SL
Bullens
Stefan
S
Seeber
Maria E
ME
Fuentes
Aran F
AF
Labrijn
Yvo M F
YM
Graus
Lisa A
LA
Miller
Edward S
ES
Schelegle
Dallas M
DM
Hyde
Lawren C
LC
Wu
Sarah G
SG
Hymowitz
Flavius
F
Martin
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D006224:Cricetinae; D016207:Cytokines / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007073:Immunoglobulin E / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D053278:OX40 Ligand / Q000037:antagonists & inhibitors* / Q000276:immunology; D053262:Receptors, OX40 / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
D000911:Antibodies, Monoclonal; D016207:Cytokines; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; C089251:TNFSF4 protein, human; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D007073:Immunoglobulin E; D000094632:Thymic Stromal Lymphopoietin