July-August 2012, Volume 9, Issue 4
Can You Stand It? How Bone Marrow Transplants Can Make Unmatched Renal Allografts Tolerable
Published on: July 01, 2012
Dr. Vercellotti indicated no relevant conflicts of interest.
Study Title: Induction of Donor Specific Tolerance in Recipients of Living Kidney Allografts by Donor Stem Cell Infusion
ClinicalTrials.gov Identifier: NCT00497926
Study Sponsor: University of Louisville
Collaborators: Northwestern University, Department of Defense (OAR), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Principal Investigator: Joseph Leventhal, MD, Northwestern Memorial Hospital
Accrual Goal: 30
Study Design: This is a phase II, non-randomized trial to assess safety and efficacy. The current trial utilizes a non-myeloablative preparative regimen that incorporates infusion of hematopoietic stem cells along with graft tolerance-promoting-facilitating cells (FCRx). These tolerance-promoting cells are CD8+ but do not express the T-cell receptor. The kidney from the living donor is transplanted on Day 0 of the hematopoietic stem cell transplantation. Patients must be between the ages of 18 and 65 years old and meet the institution’s criteria for renal transplantation for end-organ failure. Primary outcome includes bone marrow engraftment and chimerism, while characterization of graft-versus-host disease (GVHD) is a secondary outcome.
Rationale: The aim of this study is to determine whether administration of donor-derived, G-CSF-mobilized peripheral blood cells, enriched for both hematopoietic stem cells and graft-facilitating cells and depleted of GVHD-producing T cells, will induce immune tolerance of mismatched renal allografts from living related or unrelated donors. In a recent report, five of eight kidney transplant recipients who underwent this procedure were taken off immunosuppressive agents by one year with no evidence of GVHD or engraftment syndrome (Leventhal J et al. Sci Transl Med. 2012;4:124ra28).
Comment: From the time of Medawar and Billingham and the first kidney transplants of Murray, the goal of developing a method that would allow donor organ acceptance in the absence of chronic immunosuppression has remained elusive. Despite identification of several successful approaches in mice, in adult humans, attempts to induce tolerance to solid organs transplanted across MHC barriers have produced inconsistent results. In the animal studies, demonstration of hematopoietic chimerism that included lymphocytes that neither rejected the transplanted organ nor attacked the recipient in a GVH-like reaction defined tolerance. In humans who received a bone marrow transplant and subsequently a kidney transplant from the same donor, this same definition of tolerance was observed even in the absence of immunosuppressive therapy. The prospective trial described herein weds basic immunology with transplantation science resulting in an exciting new approach to ameliorating the adverse consequences of mismatched renal allografts and minimizing (or eliminating) chronic immunosuppressive therapy, reducing the incidence of renal toxicity, drug-induced diabetes, post-transplant malignancy, hypertension, cardiovascular disease, and opportunistic infections. Conceivably, by inducing immune tolerance through use of non-myeloablative hematopoietic stem cell transplant, successful allografting of mismatched recipients may prove applicable in settings beyond renal transplant.
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