LATE BREAKING II

J.R. Leventhal¹, L. Gallon¹, J. Miller², M. Abecassis¹, K. Ravindra³, E. Reed⁴, S.T. Ildstad^4
1Comprehensive Transplant Center, NORTHWESTERN UNIVERSITY, CHICAGO/UNITED STATES OF AMERICA, ²Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago/UNITED STATES OF AMERICA, ³Institute For Cellular Therapeutics, University of Louisville, Louisville/UNITED STATES OF AMERICA, ⁴University Of Louisville, Institute for Cellular Therapeutics, Louisville/KY/UNITED STATES OF AMERICA

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Introduction: Renal transplantation is the preferred therapeutic approach for end stage renal disease. However, the chronic use of nonspecific immunosuppressive agents (IS) is costly and has significant toxicities including opportunistic infection, an increased rate of malignancy, nephrotoxicity, and other end organ damage. The induction of donor-specific tolerance would address these limitations. Bone marrow chimerism induces tolerance to transplanted organs and tissues. However, the toxicity associated with conventional hematopoietic stem cell transplants (HSCT), primarily graft versus-host disease (GVHD), and the need for aggressive ablative conditioning, has limited the therapeutic application of HSCT to tolerance induction. We have identified a novel tolerogenic bone marrow cell population of CD8+/TCR- facilitating cells (FC) that enhances engraftment of bone marrow in mismatched recipients without causing GVHD. The discovery of FC is an important finding as it opens the door to employing HSCT as a viable cell-based approach for tolerance induction. Methods: 7 HLA mismatched living donor renal transplant recipients have been entered into a tolerogenic protocol involving nonmyeloablative conditioning (fludarabine, cyclophosphamide, 200cGy TBI days -4 to -1). Patients received a living donor kidney transplant on day 0, followed by infusion of cryopreserved FC-enriched CD34+ hematopoietic stem cells on Day +1 ( 0.49 to 4.48 X10⁶ FC/kg recipient body weight). All subjects were discharged by post operative day 3 and managed as outpatients. Maintenance IS consisted of tacrolimus and MMF without steroids. Results: The first 7 patients are now 16, 14, 12, 11, ,4-,3-, and 2 months post-Tx. All pts demonstrated macrochimerism post-Tx, ranging from 25% to 100% at 1 month. 3 pts with > 6 months f/u have evidence of donor-specific hyporesponsiveness and are being weaned from IS. Patients are immunocompetent to respond to mitogen (PHA), MHC-disparate third party alloantigen, and tetanus in in vitro proliferative assays. None of our pts have developed GVHD. None of the patients developed anti-donor antibody as assessed by flow crossmatch. One patient developed aplastic anemia following an atypical viral infection 2 months post-Tx, requiring rescue with banked autologous HSCT. Conclusions: Nonmyeloablative conditioning in conjunction with FC enriched HSCT can safely achieve durable mixed chimerism in kidney transplant recipients, allowing for IS withdrawal.

Disclosure: All authors have declared no conflicts of interest.