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Presenter: Suzanne T., Ildstad, Louisville, KY, USA
Authors: Joseph Leventhal, Michael Abecassis, Joshua Miller, Lorenzo Gallon, Kadiyala Ravindra, Roger Herzig, David J. Tollerud, Bradley King, Suzanne T. Ildstad
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.
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