Anti-CD40 monoclonal antibody synergizes with CTLA4-Ig in promoting long-term graft survival in murine models of transplantation.
Blockade of the CD40/CD154 signaling pathway using anti-CD154 Abs has shown promise in attenuating the alloimmune response and promoting long-term graft survival in murine model systems, although side effects observed in humans have hampered its progression through clinical trials. Appropriately designed anti-CD40 Abs may provide a suitable alternative. We investigated two isoforms of a novel monoclonal rat anti-mouse CD40 Ab (7E1) for characteristics and effects mirroring those of anti-CD154: 7E1-G1 (an IgG1 isotype); and 7E1-G2b (an IgG2b isotype). In vitro proliferation assays to measure the agonist properties of the two anti-CD40 Abs revealed similar responses when plate bound. However, when present as a soluble stimulus, 7E1-G1 but not 7E1-G2b led to proliferation. 7E1-G2b was as effective as anti-CD154 when administered in vivo in concert with CTLA4-Ig in promoting both allogeneic bone marrow chimerism and skin graft survival, whereas 7E1-G1 was not. The protection observed with 7E1-G2b was not due to depletion of CD40-bearing APCs. These data suggest that an appropriately designed anti-CD40 Ab can promote graft survival as well as anti-CD154, making 7E1-G2b an attractive substitute in mouse models of costimulation blockade-based tolerance regimens.
Gilson
Christopher R
CR
Department of Surgery and Emory Transplant Center, Emory University, Atlanta, GA 30322, USA.
Milas
Zvonimir
Z
Gangappa
Shivaprakash
S
Hollenbaugh
Diane
D
Pearson
Thomas C
TC
Ford
Mandy L
ML
Larsen
Christian P
CP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006085:Graft Survival / Q000187:drug effects*; D007108:Immune Tolerance / Q000187:drug effects; D007136:Immunoglobulins / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D023421:Models, Animal; D016038:Skin Transplantation / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology* / Q000379:methods
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C556708:Ctla4 protein, rat; D007136:Immunoglobulins