title: HLA identical non-chimeric and HLA disparate chimeric renal transplant tolerance.
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 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 Those with non-durable chimerism have not been able to have immunosuppression withdrawn but maintain normal renal transplant function.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.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Leventhal
authors.forename: James M
authors.initials: JM
authors.lastname: Mathew
authors.forename: Suzanne
authors.initials: S
authors.lastname: Ildstad
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Salomon
authors.forename: Sunil M
authors.initials: SM
authors.lastname: Kurian
authors.forename: Manikkam
authors.initials: M
authors.lastname: Suthanthiran
authors.forename: Anat
authors.initials: A
authors.lastname: Tambur
authors.forename: John
authors.initials: J
authors.lastname: Friedewald
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gallon
authors.forename: Jane
authors.initials: J
authors.lastname: Charette
authors.forename: Josh
authors.initials: J
authors.lastname: Levitsky
authors.forename: Yashpal
authors.initials: Y
authors.lastname: Kanwar
authors.forename: Michael
authors.initials: M
authors.lastname: Abecassis
authors.forename: Joshua
authors.initials: J
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D023281:Genomics; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016130:Immunophenotyping; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014019:Tissue Donors; D018183:Transplantation Chimera / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D006680:HLA Antigens