Combined effects of calcineurin inhibitors or sirolimus with anti-CD40L mAb on alloengraftment under nonmyeloablative conditions.
The immunosuppressive drugs, cyclosporine A (CsA), tacrolimus, or sirolimus, were analyzed as single agents and in combination with anti-CD40L monoclonal antibody (mAb) for their effects on alloengraftment in mice conditioned with minimal total body irradiation (TBI). Whereas anti-CD40L mAb facilitated chimerism, neither sirolimus nor CsA resulted in substantial alloengraftment. However, sirolimus was synergistic with anti-CD40L mAb for inducing donor chimerism. Contrary to expectations, CsA, a T-cell receptor (TCR) signaling inhibitor, did not abrogate anti-CD40L mAb-facilitated engraftment but rather increased engraftment in anti-CD40L mAb-treated mice. Although tacrolimus alone or with anti-CD40L mAb resulted in similar levels of donor chimerism, donor T-cell reconstitution was very low in tacrolimus-treated mice. At 1 week after transplantation, CsA decreased thymic numbers more profoundly than sirolimus or tacrolimus in anti-CD40L mAb-treated recipients. In contrast, only sirolimus resulted in a decrease in host splenic T-cell numbers in anti-CD40L mAb-treated recipients. Importantly, sirolimus and anti-CD40L mAb induced profound donor tolerance with 100% acceptance of donor skin grafts placed early after bone marrow transplantation (BMT). In contrast, anti-CD40L mAb alone or in combination with CsA resulted in 12% or less donor skin graft acceptance early (1 month) and 60% or less later (3 months) after BMT. These data have clinical relevance and indicate that immunosuppressive pharmacologic agents enhance anti-CD40L mAb-facilitated alloengraftment and tolerance induction under nonmyeloablative conditioning.
Taylor
Patricia A
PA
University of Minnesota Cancer Center, Division of Bone Marrow Transplantation, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Lees
Christopher J
CJ
Wilson
Jessica M
JM
Ehrhardt
Michael J
MJ
Campbell
Matthew T
MT
Noelle
Randolph J
RJ
Blazar
Bruce R
BR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand / Q000276:immunology*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D006085:Graft Survival / Q000187:drug effects*; D006086:Graft vs Host Disease / Q000517:prevention & control; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D016038:Skin Transplantation / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology* / Q000627:therapeutic use; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus