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

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.

• Authors: Rajaraman Eri, Krithika N Kodumudi, Don John Summerlin, Mythily Srinivasan
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 14 Issue 4 Pg. 458-70 (Apr 2008) ISSN: 1078-0998 [Print] England
• PMID: 18186109 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• B7-1 Antigen
• CD80-CAP
• Cytokines
• Oligopeptides
• Trinitrobenzenesulfonic Acid

Topics

• Adoptive Transfer
• Animals
• B7-1 Antigen (immunology)
• Binding, Competitive
• Colitis (chemically induced, etiology, pathology, prevention & control)
• Colon (metabolism, pathology)
• Cytokines (metabolism)
• Female
• Inflammation
• Inflammatory Bowel Diseases (immunology, metabolism, pathology)
• Lymphocyte Activation
• Mice
• Mice, Inbred C57BL
• Mice, SCID
• Oligopeptides (therapeutic use)
• T-Lymphocytes (immunology)
• Trinitrobenzenesulfonic Acid