HLA identical non-chimeric and HLA disparate chimeric renal transplant tolerance

In this chapter, we describe studies on non-chimeric human leukocyte antigen (HLA) identical tolerance and chimeric HLA disparate tolerance brought about by infusions of hematopoietic stem cells from the renal donor (DHSC). In our HLA identical series, 4 DHSC infusions were administered during the first 9 months posttransplant in a highly immunoregulatory environment using alemtuzumab induction and rapid conversion from early tacrolimus to mycophenolate and sirolimus. This resulted in the generation of recipient T regulatory cells accompanied by genomic indicators, but only transient chimerism. Seven of the first 12 recipients have been immunosuppression-free between 1 1/2 - 4 years with transplant biopsies free of rejection one year after immunosuppression withdrawal. The HLAdisparate group was treated by non-myeloablative conditioning consisting of: 200cGy whole body irradiation; fludarabine; cyclophosphamide; and, perioperative infusion of a product termed FCRx that contained DHSC, T cells, and a unique fraction of bone marrow derived CD8+TCR-alphabeta-negative cells. Five of the first 8 subjects became 100% chimeric in the peripheral blood and have been immunosuppression-free for 2 to 4 years without graft-versus-host-disease and with normal function and transplant biopsies. An additional 12 recipients with shorter follow-up have had similar courses. Those with non-durable chimerism have not been able to have immunosuppression withdrawn but maintain normal renal transplant function. We conclude that non-HLA disparities in renal transplants between HLA identical pairs may not need durable chimerism to induce tolerance provided by DHSC and temporary immunosuppression supporting the development of regulatory T cells. However, more intense conditioning and infusion of FCRx leading to durable chimerism in the absence of graft versus host disease is necessary to induce tolerance in HLA disparate pairs.