title: Anti-complement component C5 mAb synergizes with CTLA4Ig to inhibit alloreactive T cells and prolong cardiac allograft survival in mice.
abstract: While activation of serum complement mediates antibody-initiated vascular allograft injury, increasing evidence indicates that complement also functions as a modulator of alloreactive T cells. We tested whether blockade of complement activation at the C5 convertase step affects T cell-mediated cardiac allograft rejection in mice. The anti-C5 mAb BB5.1, which prevents the formation of C5a and C5b, synergized with subtherapeutic doses of CTLA4Ig to significantly prolong the survival of C57BL/6 heart grafts that were transplanted into naive BALB/c recipients. Anti-C5 mAb treatment limited the induction of donor-specific IFNγ-producing T cell alloimmunity without inducing Th2 or Th17 immunity in vivo and inhibited primed T cells from responding to donor antigens in secondary mixed lymphocyte responses. Additional administration of anti-C5 mAb to the donor prior to graft recovery further prolonged graft survival and concomitantly reduced both the in vivo trafficking of primed T cells into the transplanted allograft and decreased expression of T cell chemoattractant chemokines within the graft. Together these results support the novel concept that C5 blockade can inhibit T cell-mediated allograft rejection through multiple mechanisms, and suggest that C5 blockade may constitute a viable strategy to prevent and/or treat T cell-mediated allograft rejection in humans.
authors.affiliation: Division of Nephrology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Raedler
authors.forename: M B
authors.initials: MB
authors.lastname: Vieyra
authors.forename: S
authors.initials: S
authors.lastname: Leisman
authors.forename: P
authors.initials: P
authors.lastname: Lakhani
authors.forename: W
authors.initials: W
authors.lastname: Kwan
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.forename: K
authors.initials: K
authors.lastname: Johnson
authors.forename: S J
authors.initials: SJ
authors.lastname: Faas
authors.forename: P
authors.initials: P
authors.lastname: Tamburini
authors.forename: P S
authors.initials: PS
authors.lastname: Heeger
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003182:Complement C5 / Q000276:immunology*; D004357:Drug Synergism; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D003182:Complement C5; D018796:Immunoconjugates; D000069594:Abatacept