title: Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.
abstract: The toxicity of chronic immunosuppressive agents required for organ transplant maintenance has prompted investigators to pursue approaches to induce immune tolerance. We developed an approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (HSCs) and tolerogenic graft facilitating cells (FCs) combined with nonmyeloablative conditioning; this approach resulted in engraftment, durable chimerism, and tolerance induction in recipients with highly mismatched related and unrelated donors. Eight recipients of human leukocyte antigen (HLA)-mismatched kidney and FC/HSC transplants underwent conditioning with fludarabine, 200-centigray total body irradiation, and cyclophosphamide followed by posttransplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match ranged from five of six loci with related donors to one of six loci with unrelated donors. The absolute neutrophil counts reached a nadir about 1 week after transplant, with recovery by 2 weeks. Multilineage chimerism at 1 month ranged from 6 to 100%. The conditioning was well tolerated, with outpatient management after postoperative day 2. Two subjects exhibited transient chimerism and were maintained on low-dose tacrolimus monotherapy. One subject developed viral sepsis 2 months after transplant and experienced renal artery thrombosis. Five subjects experienced durable chimerism, demonstrated immunocompetence and donor-specific tolerance by in vitro proliferative assays, and were successfully weaned off all immunosuppression 1 year after transplant. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome or graft-versus-host disease. These results suggest that manipulation of a mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing durable chimerism and donor-specific tolerance in solid organ transplant recipients.
authors.affiliation: Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, IL 60611, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Leventhal
authors.forename: Michael
authors.initials: M
authors.lastname: Abecassis
authors.forename: Joshua
authors.initials: J
authors.lastname: Miller
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gallon
authors.forename: Kadiyala
authors.initials: K
authors.lastname: Ravindra
authors.forename: David J
authors.initials: DJ
authors.lastname: Tollerud
authors.forename: Bradley
authors.initials: B
authors.lastname: King
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Elliott
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Herzig
authors.forename: Roger
authors.initials: R
authors.lastname: Herzig
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Ildstad
mesh_terms: D000328:Adult; D006086:Graft vs Host Disease / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use
chemical_list: D006680:HLA Antigens; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus