Suppression of immune responses in collagen-induced arthritis by a rationally designed CD80-binding peptide agent
| Autor: | Don John Summerlin, David D. Brand, Rajaraman Eri, Susan L. Zunt, Mythily Srinivasan, Janice S. Blum |
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| Rok vydání: | 2007 |
| Předmět: |
CD4-Positive T-Lymphocytes
T cell Immunology Type II collagen Arthritis Apoptosis chemical and pharmacologic phenomena Pharmacology Binding Competitive Arthritis Rheumatoid Mice Immune system Rheumatology Antigens CD In vivo Cell Line Tumor Animals Humans Immunology and Allergy Medicine CTLA-4 Antigen Pharmacology (medical) Interleukin 6 Cells Cultured biology Interleukin-6 business.industry Synovial Membrane hemic and immune systems medicine.disease Antigens Differentiation Disease Models Animal Mononuclear cell infiltration medicine.anatomical_structure Neutrophil Infiltration Mice Inbred DBA Immune System B7-1 Antigen biology.protein Cytokines Female Collagen Peptides business CD80 |
| Zdroj: | Arthritis & Rheumatism. 56:498-508 |
| ISSN: | 1529-0131 0004-3591 |
| DOI: | 10.1002/art.22324 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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