title: Alloimmunity in primate heart recipients with CD154 blockade: evidence for alternative costimulation mechanisms.
abstract: BACKGROUND
  CD154 mediates key facets of humoral and cellular immunity to alloantigens, and is tolerogenic to influenza antigens in primates. Barriers to CD154-based tolerance induction for primate cardiac allografts have not previously been defined.
  
  
  METHODS
  Heterotopic cardiac allograft outcomes in cynomolgus monkeys treated with a CD154 inhibitor, IDEC-131 (n=27), were compared to no treatment (n=4) or cyclosporine A (n=6).
  
  
  RESULTS
  CD154 blockade significantly prolonged median allograft survival, from 6.2 (range 6, 7, n=4) days in untreated controls, to 39 (8,112, n=16) days with intensive monotherapy and 93 (>25, 386; n=3) days with added antithymocyte globulin (ATG), but did not yield tolerance. Alloantibody production was delayed but not prevented by IDEC-131 alone or with ATG, and was exacerbated by infusion of donor bone marrow (n=8). Expression of ICOS was prominent in graft infiltrating lymphocytes, and preceded elaboration of antidonor antibody and vasculopathy.
  
  
  CONCLUSIONS
  CD154 monotherapy modulates primate cardiac alloimmunity, but does not readily induce tolerance. Targeting alternative costimulation pathways, including ICOS, may facilitate tolerance induction based on CD154 blockade.
authors.affiliation: Division of Cardiac Surgery, University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA. aazimzadeh@smail.umaryland.edu
authors.forename: Agnes M
authors.initials: AM
authors.lastname: Azimzadeh
authors.forename: Steffen
authors.initials: S
authors.lastname: Pfeiffer
authors.forename: Guosheng
authors.initials: G
authors.lastname: Wu
authors.forename: Carsten
authors.initials: C
authors.lastname: Schröder
authors.forename: George L
authors.initials: GL
authors.lastname: Zorn
authors.forename: Shahrooz S
authors.initials: SS
authors.lastname: Kelishadi
authors.forename: Engin
authors.initials: E
authors.lastname: Ozkaynak
authors.forename: Marilyn
authors.initials: M
authors.lastname: Kehry
authors.forename: James B
authors.initials: JB
authors.lastname: Atkinson
authors.forename: Geraldine G
authors.initials: GG
authors.lastname: Miller
authors.forename: Richard N
authors.initials: RN
authors.lastname: Pierson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D060889:Inducible T-Cell Co-Stimulator Protein; D007518:Isoantibodies / Q000096:biosynthesis; D008252:Macaca fascicularis; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D060889:Inducible T-Cell Co-Stimulator Protein; D007518:Isoantibodies; D023201:CD40 Ligand; D016572:Cyclosporine; C470330:toralizumab