Chimerism and Tolerance in HLA-Mismatched Renal/Stem Cell Transplantation

Joseph Leventhal¹, Michael Abecassis¹, Joshua Miller¹, Lorenzo Gallon¹, Kadiyala Ravindra², Roger Herzig², David J. Tollerud², Bradley King², Suzanne T. Ildstad².

¹Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, IL, USA; ²Institute for Cellular Therapeutics, University of Louisville, Louisville, KY, USA.

Background: Mixed chimerism has been suggested as an approach to induce tolerance and eliminate the need for chronic immunosuppression in solid organ transplantation. We developed an approach using a mobilized cellular product enriched for hematopoietic stem cells and facilitating cells combined with nonmyeloablative conditioning that allows engraftment, durable mixed chimerism, and tolerance induction in highly mismatched donor-recipient pairs.

Methods:The transplant conditioning consisted of fludarabine, 200 cGy total body irradiation, and cyclophosphamide followed by post-transplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged from 29 to 56 years of age. HLA match ranged from 5 of 6 related to 1 of 6 unrelated. If chimerism and/or tolerance were present at 6 months, the MF was discontinued. At 9 months trough levels of tacrolimus are maintained at 0-3. The tacrolimus is discontinued at 12 months.

Results: We describe 8 recipients of HLA-mismatched combined kidney and hematopoietic cell transplants > 6 months post-transplant. The nadir neutrophil counts occurred approximately one week post-transplant, with recovery by 2 weeks. Recipients were discharged on post-operative day 2 and managed as outpatient. Multilineage chimerism at 1 month ranged from 6% to 100%. The conditioning was well tolerated and the subjects were managed as outpatients after post-operative day 2. Five subjects have durable chimerism, with immunocompetence and donor-specific tolerance by in vitro proliferative assays. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome. Four of the recipients have been reduced to maintenance low-dose tacrolimus monotherapy and one has been successfully weaned off all immunosuppression at one year post-transplant. No subject has developed graft-versus-host disease. All have stable renal function.

Conclusion: These initial results suggest that manipulation of a peripherally mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing donor specific tolerance in solid organ transplant recipients.