HLA Identical Non-Chimeric and HLA Disparate Chimeric Renal Transplant Tolerance.
Leventhal JR, Mathew JM, Ildstad S, Salomon DR, Kurian SM, Suthanthiran M, Tambur A, Friedewald J, Gallon L, Charette J, Levitsky J, Kanwar Y, Abecassis M, Miller J.
Clinical Transplants 2013, Chapter 17
Abstract
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 CD8TCR-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 Those with non-durable chimerism have not been able to have immunosuppression withdrawn but maintain normal renal transplant function.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.
