title: A novel CD154 monoclonal antibody in acute and chronic rat vascularized cardiac allograft rejection.
abstract: BACKGROUND
  The CD40-CD154 interaction is critically important in the cell-mediated immune responses. Blockade of this costimulatory pathway has been shown to prevent acute allograft rejection in murine, as well as nonhuman primate models. However, the role of the CD40-CD154 pathway in the development of chronic rejection and the effects of CD154 targeting on progression of chronic rejection have not been evaluated.
  
  
  METHODS
  We examined the effect of AH.F5, a new hamster anti-rat CD154 monoclonal antibody, in a fully allogeneic acute(u) into Lewis [LEW] (RT11) and chronic [WF.1L (RT1l) into LEW (RT1l)] vascularized cardiac allograft rejection model. In the chronic model, the antibody was evaluated for prevention (starting day of transplant) and interruption of progression (starting day 30 or 60 after transplant) of chronic vasculopathy. Graft survival, morphology, and immunohistology were evaluated.
  
  
  RESULTS
  In the acute rejection model, anti-CD154 therapy alone prevented acute allograft rejection and resulted in 50% long-term allograft survival (>200 days) and donor-specific tolerance. In recipients treated with anti-CD154 monoclonal antibody in combination with a short course of cyclosporine, 100% of allografts survived long-term and all recipients achieved donor-specific tolerance. In the chronic rejection model, allografts from animals treated with the anti-CD154 antibody had a statistically significant lower score of graft arteriosclerosis and fibrosis in both the prevention and 30-day interruption groups when compared with control allografts. In addition, immunohistochemistry showed a decrease in intragraft mononuclear cell infiltration and activation.
  
  
  CONCLUSIONS
  A new anti-CD154 antibody not only prevents acute allograft rejection, but also inhibits and interrupts the development of chronic rejection. In the acute rejection model cyclosporine acts synergistically with anti-CD154 therapy to prolong allograft survival and induce tolerance. In the chronic rejection model relatively early initiation of therapy is essential to prevent progression of chronic allograft vasculopathy and fibrosis.
authors.affiliation: Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, U.S.A.
authors.forename: Xueli
authors.initials: X
authors.lastname: Yuan
authors.forename: Victor M
authors.initials: VM
authors.lastname: Dong
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Coito
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Waaga
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Benjamin
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Anil
authors.initials: A
authors.lastname: Chandraker
mesh_terms: D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000187:drug effects; D023201:CD40 Ligand / Q000032:analysis / Q000276:immunology*; D002908:Chronic Disease; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000628:therapy*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007167:Immunotherapy; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D012260:Ribonucleases; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D016572:Cyclosporine; D012260:Ribonucleases