CD80 blockade enhance glucocorticoid-induced leucine zipper expression and suppress experimental autoimmune encephalomyelitis.
Designing mimetic of the interface functional groups of known receptor-ligand complexes is an attractive strategy for developing potential therapeutic agents that interfere with target protein-protein interactions. The CD80/CD86-CD28/CD152 costimulatory interactions transmit signals for CD4(+) T cell activation and suppression and are critically involved in the initiation, progression, and reactivation of the immunopathology in multiple sclerosis. Differences in the pattern, levels, and kinetics of expression of CD80/CD86 molecules in conjunction with differences in the strength of the signals delivered upon binding CD28 or CD152 determine the outcome of the immune response. A temporal up-regulation of surface expression of CD80 relative to CD86 on APCs and CNS-infiltrating cells has been shown to correlate with disease progression in experimental autoimmune encephalomyelitis an animal model for multiple sclerosis. Hence blockade of the CD80 costimulatory axis has therapeutic potential in multiple sclerosis. In this study, we report the efficacy of a novel CD80-blocking agent CD80-competitive antagonist peptide (CD80-CAP) in suppressing clinical disease and relapse in experimental autoimmune encephalomyelitis. The CD80-CAP mediates protection by inhibiting proinflammatory cytokines and skewing toward anti-inflammatory response presumably by enhancing the expression of glucocorticoid-induced leucine zipper in activated CD4(+) T cells.
Dudhgaonkar
Shailesh P
SP
Department of Oral Pathology, Medicine and Radiology, School of Dentistry, Indiana University-Purdue University, Indianapolis, IN 46202, USA.
Janardhanam
Srihari B
SB
Kodumudi
Krithika N
KN
Srinivasan
Mythily
M
D000818:Animals; D018122:B7-1 Antigen / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000276:immunology / Q000494:pharmacology; D016350:Leucine Zippers / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C530950:CD80-CAP; C497965:Cd86 protein, mouse; D016207:Cytokines; D005938:Glucocorticoids; D009842:Oligopeptides