Source
Department of Oral Pathology, Medicine and Radiology, School of Dentistry, Indiana University Purdue University at Indianapolis, Indianapolis, Indiana 46202, USA.
Abstract
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+CD45Rb(high) 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.