title: Suppression of immune responses in collagen-induced arthritis by a rationally designed CD80-binding peptide agent.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Indiana University, Indianapolis, and Indiana University-Purdue University, IN 46202, USA. mysriniv@iupui.edu
authors.forename: Mythily
authors.initials: M
authors.lastname: Srinivasan
authors.forename: Rajaraman
authors.initials: R
authors.lastname: Eri
authors.forename: Susan L
authors.initials: SL
authors.lastname: Zunt
authors.forename: Don-John
authors.initials: DJ
authors.lastname: Summerlin
authors.forename: David D
authors.initials: DD
authors.lastname: Brand
authors.forename: Janice S
authors.initials: JS
authors.lastname: Blum
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism*; D001667:Binding, Competitive; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D060908:CTLA-4 Antigen; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003094:Collagen; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007107:Immune System / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008811:Mice, Inbred DBA; D020556:Neutrophil Infiltration / Q000187:drug effects; D010455:Peptides / Q000737:chemistry; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D016207:Cytokines; D015850:Interleukin-6; D010455:Peptides; D003094:Collagen