title: Role of the Fc region in CD70-specific antibody effects on cardiac transplant survival.
abstract: BACKGROUND
  The role of the CD70-specific antibody and the mechanisms by which it extends transplant survival are not known.
  
  
  METHODS
  Fully major histocompatibility complex-mismatched heterotopic heart transplantation (BALB/c to C57BL/6) was performed. Treated mice received intraperitoneal injections of wild-type (WT) CD70-specific antibody (FR70) or IgG1 or IgG2a chimeric antibodies on days 0, 2, 4, and 6 posttransplantation.
  
  
  RESULTS
  WT FR70 antibody significantly extended heart transplant survival to 19 days compared with untreated mice (median survival time [MST]=10 days). Graft survival using the nondepleting IgG1 antibody was significantly shorter (MST=14 days), whereas the survival using depleting IgG2a antibody (MST=18) was similar to that using WT FR70. The FR70 and IgG2a antibodies demonstrated a greater efficiency of fixing mouse complement over the IgG1 variant in vitro. CD4 and CD8 T-cell graft infiltration was reduced with treatment; however, this was most pronounced with WT FR70 and IgG2a antibody therapy compared with the IgG1 chimeric variant. Circulating donor-specific IgG alloantibodies were initially reduced with WT FR70 treatment (day 8 posttransplantation) but increased at days 15 and 20 posttransplantation to the level detected in untreated controls.
  
  
  CONCLUSIONS
  We conclude that WT (FR70) and the IgG2a depleting variant of CD70-specific antibody reduce graft infiltrating CD4 and CD8 T cells, transiently reduce serum alloantibody levels, and extend graft survival. In contrast, the nondepleting IgG1 variant of this antibody showed lower efficacy. These data suggest that a depleting mechanism of action and not merely costimulation blockade plays a substantial role in the therapeutic effects of CD70-specific antibody.
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, King's College London, Guy's Hospital, London, UK.
authors.forename: Hina
authors.initials: H
authors.lastname: Shariff
authors.forename: Roseanna E
authors.initials: RE
authors.lastname: Greenlaw
authors.forename: Lucy
authors.initials: L
authors.lastname: Meader
authors.forename: Nicola
authors.initials: N
authors.lastname: Gardner
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Marco
authors.initials: M
authors.lastname: Coccia
authors.forename: Nizam
authors.initials: N
authors.lastname: Mamode
authors.forename: Stipo
authors.initials: S
authors.lastname: Jurcevic
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology*; D000918:Antibody Specificity / Q000276:immunology*; D053282:CD27 Ligand / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007518:Isoantibodies / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D053282:CD27 Ligand; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007518:Isoantibodies