Suppression of experimental autoimmune encephalomyelitis using peptide mimics of CD28.
The B7:CD28/CTLA-4 costimulatory pathway plays a critical role in regulating the immune response and thus provides an ideal target for therapeutic manipulation of autoimmune disease. Previous studies have shown that blockade of CD28 signaling by mAbs can both prevent and exacerbate experimental autoimmune encephalomyelitis (EAE). In this study, we have designed two CD28 peptide mimics that selectively block B7:CD28 interactions. By surface plasmon resonance, both the end group-blocked CD28 peptide (EL-CD28) and its retro-inverso isomer (RI-CD28) compete effectively with the extracellular domain of CD28 for binding to B7-1. Both the CD28 peptide mimics inhibited expansion of encephalitogenic T cells in vitro. A single administration of EL-CD28 or RI-CD28 peptide significantly reduced disease severity in EAE. Importantly, we show that either CD28 peptide mimic administered during acute disease dramatically improved clinical signs of EAE, suppressing ongoing disease. The ratio of CD80:CD86 expression was significantly lower on CD4(+) and F4/80(+) spleen cells in CD28 peptide-treated mice. Peripheral deletion of Ag-specific CD4(+) T cells occurs following in vivo blockade of CD28 with synthetic CD28 peptides.
Srinivasan
Mythily
M
Department of Microbiology, College of Biological Sciences, Ohio State University, Columbus, OH 43210, USA.
Gienapp
Ingrid E
IE
Stuckman
Scott S
SS
Rogers
Connie J
CJ
Jewell
Scott D
SD
Kaumaya
Pravin T P
PT
Whitacre
Caroline C
CC
D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D001665:Binding Sites; D001667:Binding, Competitive; D018106:CD28 Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D060908:CTLA-4 Antigen; D015195:Drug Design; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D018796:Immunoconjugates; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D010455:Peptides; D000069594:Abatacept