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Suppression of colon inflammation by CD80 blockade: Evaluation in two murine models of inflammatory bowel disease

Eri, Rajaraman PhD1,*; Kodumudi, Krithika N. PhD1; Summerlin, Don John MS1; Srinivasan, Mythily MDS, PhD1,*

doi: 10.1002/ibd.20344
Original Basic Science Articles

Background:: Human inflammatory bowel disease (IBD) is a chronic condition mediated by aberrant immune responses to the luminal antigens by activated CD4+ T cells. The CD80/CD86:CD28/CD152 costimulatory pathways transmit signals critical for T cell activation and suppression. Macrophages and epithelial cells are the chief antigen‐presenting cells in the gut. Macrophages from the IBD colon express significantly elevated levels of CD80 and CD86 costimulatory molecules. The CD28‐CD80 interaction primarily participates in breaking the tolerance and inducing the immune response in murine models of colitis. Blockade of CD80‐costimulatory axis is an attractive strategy in the treatment of IBD.

Methods:: Incorporating the structural information of the CD80:CD152 complex together with the preferences of interface residues to form polyproline type II helix, we designed novel peptide agents that selectively blocked CD80 receptor interactions.

Results:: Administration of CD80 blocking agent at the time of adoptive transfer prevented the SCID mice from CD4+CD45Rbhigh T‐cell mediated colitis. Significantly, CD80‐CAP (competitive antagonist peptide) treatment suppressed established inflammation in TNBS‐induced colitis, a model for Th1‐mediated Crohn's disease. The colons of the mice receiving the CD80 blocking agent appeared unaffected macroscopically and exhibited negligible microscopic inflammation. The CD80‐CAP treatment was associated with significantly reduced Th1 cytokines in the colon.

Conclusions:: The CD80 blocking peptide appeared to mediate protection against colitis by inducing Th2 skewing of the cytokine response.

1Department of Oral Pathology, Medicine and Radiology, School of Dentistry, Indiana University Purdue University at Indianapolis, Indianapolis, Indiana

*IBD Research Team, Mater Medical Research Institute, Raymond Terrace, Aubugny Place, South Brisbane Q 4101, Australia

* Department of Oral Pathology, Medicine and Radiology, 1121 W. Michigan St., Indianapolis, IN 46202 (e‐mail: mysriniv@iupui.edu)

Received 27 July 2007; Accepted 22 October 2007

Published online 9 January 2008 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: National Institutes of Health; Grant Number: RO3 AR051411‐01; Grant sponsor: ‘First Award’ by Crohn's and Colitis Foundation of America.

© Crohn's & Colitis Foundation of America, Inc.
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