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Suppression of immune responses in collagen-induced arthritis by a rationally designed CD80-binding peptide agent

Citation

Srinivasan, M and Eri, RD and Zunt, SL and Summerlin, DJ and Brand, DD and Blum, JS, Suppression of immune responses in collagen-induced arthritis by a rationally designed CD80-binding peptide agent, Arthritis & Rheumatism, 56, (2) pp. 498-508. ISSN 1529-0131 (2007) [Refereed Article]

DOI: doi:10.1002/art.22324

Abstract

Objective. The CD80/CD86-CD28/CD152 costimulatory pathways transmit signals for CD4+ T cell activation and suppression and are critically involved in the pathogenesis of rheumatoid arthritis (RA). A significant number of CD4+ T cells and macrophages in the rheumatoid synovium express elevated levels of CD80, increasing the potential for costimulation in trans of naive T cells. To determine the effect of blockade of this costimulatory axis in RA, we designed novel CD80-binding peptides and evaluated their therapeutic potential in collagen-induced arthritis (CIA), an animal model of RA. Methods. The conserved MYPPPY motif of CD152 adopts a polyproline type II (PPII) helical conformation in the CD80-CD152 complex. The pairing preferences of the critical residues at the CD80-CD152 interface and their propensity to form PPII helices were integrated to design peptides with optimum PPII helical content that selectively block CD80-receptor interactions. The clinical efficacy was tested in DBA/1LacJ mice that were administered the CD80 blocking agents, called CD80-binding competitive antagonist peptides (CD80-CAPs), at the time of immunization with bovine type II collagen or 3 weeks after immunization. Results. A single administration of select CD80-CAPs significantly reduced the clinical, radiologic, and histologic disease severity in CIA. Importantly, administration of CD80-CAPs during activated immune response significantly suppressed disease development by reducing mononuclear cell infiltration in the joints and mediating peripheral deletion of activated CD4+ T cells. Conclusion. A rationally designed CD80-binding peptide both prevents and suppresses CIA, suggesting a potential application in RA. Apoptosis of activated CD4+ T cells following in vivo blockade suggests that the effects of CD80-CAPs may be long-lasting. © 2007, American College of Rheumatology.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Genetic Immunology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Digestive System Disorders
Author:Eri, RD (Dr Raj Eri)
ID Code:67804
Year Published:2007
Web of Science® Times Cited:12
Deposited By:Health Sciences A
Deposited On:2011-03-08
Last Modified:2011-03-08
Downloads:0

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