title: Belatacept and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion.
abstract: Belatacept is an inhibitor of CD28/B7 costimulation that is clinically indicated as a calcineurin inhibitor (CNI) alternative in combination with mycophenolate mofetil and steroids after renal transplantation. We sought to develop a clinically translatable, nonlymphocyte depleting, belatacept-based regimen that could obviate the need for both CNIs and steroids. Thus, based on murine data showing synergy between costimulation blockade and mTOR inhibition, we studied rhesus monkeys undergoing MHC-mismatched renal allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on costimulation blockade-resistant rejection, some animals also received CD2 blockade with alefacept (LFA3-Ig). Belatacept and sirolimus therapy successfully prevented rejection in all animals. Tolerance was not induced, as animals rejected after withdrawal of therapy. The regimen did not deplete T cells. Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen, despite causing an intended depletion of memory T cells, and caused a marked reduction in regulatory T cells. Furthermore, alefacept-treated animals had a significantly increased incidence of CMV reactivation, suggesting that this combination overly compromised protective immunity. These data support belatacept and sirolimus as a clinically translatable, nondepleting, CNI-free, steroid-sparing immunomodulatory regimen that promotes sustained rejection-free allograft survival after renal transplantation.
authors: Emory Transplant Center, Emory University, Atlanta, GA.
authors: D J
authors: DJ
authors: Lo
authors: D J
authors: DJ
authors: Anderson
authors: T A
authors: TA
authors: Weaver
authors: F
authors: F
authors: Leopardi
authors: M
authors: M
authors: Song
authors: A B
authors: AB
authors: Farris
authors: E A
authors: EA
authors: Strobert
authors: J
authors: J
authors: Jenkins
authors: N A
authors: NA
authors: Turgeon
authors: A K
authors: AK
authors: Mehta
authors: C P
authors: CP
authors: Larsen
authors: A D
authors: AD
authors: Kirk
mesh_terms: D000069594:Abatacept; D000818:Animals; D018801:CD2 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D006084:Graft Rejection; D006085:Graft Survival; D018796:Immunoconjugates / Q000008:administration & dosage*; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000379:methods*; D008253:Macaca mulatta; D010641:Phenotype; D020123:Sirolimus / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D018801:CD2 Antigens; D017252:CD3 Complex; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D020123:Sirolimus