We recently reported anti-CD40 monoclonal antibody and rapamycin (aCD40/rapa) to be a reliable, nontoxic, immunosuppressive regimen for combined islet and kidney transplantation (CIKTx) in nonhuman primates (NHPs). In the current study, we attempted to induce allograft tolerance through the mixed chimerism approach using a conditioning regimen with aCD40 and belatacept (Bela).METHODS
Five CIKTx or kidney transplant (KTx) recipients were treated with aCD40/rapa for 4 months. All recipients then received a conditioning regimen including horse anti-thymocyte globulin (hATG) and aCD40/Bela. The results were compared with previous reports of recipients treated with Bela-based regimens.RESULTS
All 3 CIKTx recipients developed mixed chimerism, which was significantly superior to that observed in the previous Bela-based studies. Nevertheless, all CIKTx recipients in this study lost their islet and renal allografts as a result of cellular and humoral rejection on days 140, 89, and 84. The 2 KTx-alone recipients were treated with the same conditioning regimen and suffered rejection on days 127 and 116, despite the development of excellent chimerism. B lymphocyte reconstitution dominated by memory phenotypes was associated with early development of donor-specific antibodies in 4/5 recipients. In vitro assays showed no donor-specific regulatory T cell (Treg) expansion, which has been consistently observed in tolerant recipients with our mixed chimerism approach.RESULTS
Despite displaying excellent immunosuppressive efficacy, costimulatory blockade with anti-CD40 mAb (2C10R4) may inhibit the induction of renal or islet allograft tolerance via a mixed chimerism approach.