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This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0802424v1 183/1/270    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Manocha, M. Articles by Manjunath, N. PubMed PubMed Citation Articles by Manocha, M. Articles by Manjunath, N.

Blocking CD27-CD70 Costimulatory Pathway Suppresses Experimental Colitis

Monika Manocha^*, Rietdijk Svend, Amale Laouar^*, Gongxian Liao, Atul Bhan, Jannine Borst, Cox Terhorst and N. Manjunath^*

^*Department of Pediatrics, Immune Disease Institute and Harvard Medical School, Department of Immunology, Beth Israel Deaconess Medical Center and Harvard Center for Life Sciences, and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02131; and Division Of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

The pathogenesis of human inflammatory bowel disease (IBD) and most experimental models of IBD is dependent on the activation and expansion of CD4⁺ T cells via interaction with mucosal APCs. The costimulatory receptor CD70 is transiently expressed on the surface of conventional dendritic cells, but is constitutively expressed by a unique APC population in the intestinal lamina propria. We used two experimental IBD models to evaluate whether interfering the interaction between CD70 and its T cell ligand CD27 would affect the development of colitis. Adoptive transfer of naive CD27-deficient CD45RB^high CD4⁺ T cells into Rag-1^–-– mice resulted in significantly less disease than when wild-type CD45RB^highCD4⁺ T cells were used. Moreover, a monoclonal anti-CD70 Ab prevented the disease caused by the transfer of wild-type CD45RB^high CD4⁺ T cells into Rag-1^–-– mice and the same Ab also ameliorated an established disease. The colitis associated proinflammatory cytokines IL-6, TNF- and IFN- were significantly reduced after anti-CD70 Ab treatment, suggesting an overall reduction in inflammation due to blockade of pathogenic T cell expansion. Anti-CD70 Ab treatment also suppressed trinitrobenzene sulfonic acid-induced colitis in SJL/J mice. Because anti-CD70 Ab treatment suppressed multiple proinflammatory cytokines, this may be a more potent therapeutic approach for IBD than blockade of individual cytokines.

Address correspondence and reprint requests to Dr. N. Manjunath at the current address: Department of Biomedical Sciences, Paul L. Foster School of Medicine,Texas Tech University Health Sciences Center, 5001 El Paso Drive, El Paso, TX79905. E-mail address: manjunath.swamy{at}ttuhsc.edu

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