Tolerance, Mixed Chimerism, and Graft Survival in HLA Matched and Mismatched Recipients of Kidney and Hematopoietic Cell Transplants.

Abstract

Purpose: The establishment of persistent mixed chimerism, immune tolerance and the withdrawal of maintenance immunosuppressive (IS) drugs (mycophenolate mofetil and a calcineurin inhibitor) without kidney graft loss or dysfunction in clinical kidney transplantation. Methods: Thirty-seven patients were conditioned with a post-kidney transplant regimen of total lymphoid irradiation and antithymocyte globulin followed by an infusion of purified CD34+ hematopoietic progenitor cells mixed with a defined number of CD3+ T cells collected from G-CSF “mobilized” donor blood mononuclear cells. Results: Twenty-two HLA-matched and 15 HLA-mismatched patients were enrolled, and all patients have maintained good graft function at the last observation point, with follow-up to 13 years. All HLA-matched patients received an infusion of 1x106 T cells/kg, along with at least 4x106 CD34+ cells/kg, from the donors. The criteria for IS drug withdrawal were persistent mixed chimerism for at least 6 months, no clinical rejection and no subclinical rejection on surveillance biopsy, and no evidence of graft versus host disease. Of these patients, 16 have discontinued IS drugs for up to 5 years (median 3 years) without subsequent evidence of acute or chronic rejection. Five are maintained on IS drugs due to failure to meet drug withdrawal criteria (4) or relapse of lupus (1), and one is in IS drug taper. One patient off IS drugs with a history of coronary disease died during vigorous exercise. Immune monitoring of these patients showed a marked transient decrease in conventional T and B cells, an increase in the percentage of CD11b+ myeloid cells, and increase of Tregs and NKT cells among all T cells in the blood, and donor-specific unresponsiveness in the MLR indicative of tolerance. In the HLA-mismatched patients, the dose of donor T cells was escalated in order to achieve the persistent mixed chimerism observed in the HLA-matched patients. This required a marked increase in the infused dose of cells in comparison to the matched patients. Tapering of IS drugs in the HLA-mismatched patients with mixed chimerism is underway. Conclusion: Persistent mixed chimerism was achieved in both HLA-matched and HLA-mismatched patients, all kidney grafts are functioning, and thus far IS drugs were successfully withdrawn in the majority of HLA-matched patients.