Long-term Nonhuman Primate Renal Allograft Survival Without Ongoing Immunosuppression in Recipients of Delayed Donor Bone Marrow Transplantation

ABSTRACTBackgroundWe have previously reported successful induction of renal allograft tolerance in nonhuman primates (NHP) following an initial posttransplant period of conventional immunosuppression (delayed tolerance) using a nonmyeloablative conditioning regimen consisting of anti-CD154 and anti-CD8 mAbs plus equine ATG (Atgam) and donor bone marrow transplantation (DBMT). Since these reagents are not currently clinically available, the protocol was revised to be applicable to human recipients of deceased donor allografts.MethodFour cynomolgus monkeys received MHC-mismatched kidney allografts with conventional immunosuppression for 4 months. The recipients were then treated with a nonmyeloablative conditioning regimen consisting of thymoglobulin, belatacept, and DBMT. The results were compared with recipients treated with conditioning regimen consisting of Atgam and anti-CD154 mAb, with and without anti-CD8 mAb.ResultsIn 4 consecutive NHP recipients treated with the modified conditioning regimen, homeostatic recovery of CD8+ TEM was delayed until after day 20 and multilineage chimerism was successfully induced. Three of the 4 recipients achieved long-term allograft survival (>728, >540, >449 days) without ongoing maintenance immunosuppression. Posttransplant MLR showed loss of anti-donor CD8+ T cell and CD4+ IFNγ responses with expansion of CD4+FOXP3+ regulatory T cells. However, the late development of DSA in NHP recipients confirms the need for additional anti-B cell depletion with agents, such as rituximab, as has been shown in our clinical trials.ConclusionThis study provides proof of principle that induction of mixed chimerism and long-term renal allograft survival without immunosuppression after delayed donor bone marrow transplantation is possible with clinically available reagents. Background We have previously reported successful induction of renal allograft tolerance in nonhuman primates (NHP) following an initial posttransplant period of conventional immunosuppression (delayed tolerance) using a nonmyeloablative conditioning regimen consisting of anti-CD154 and anti-CD8 mAbs plus equine ATG (Atgam) and donor bone marrow transplantation (DBMT). Since these reagents are not currently clinically available, the protocol was revised to be applicable to human recipients of deceased donor allografts. Method Four cynomolgus monkeys received MHC-mismatched kidney allografts with conventional immunosuppression for 4 months. The recipients were then treated with a nonmyeloablative conditioning regimen consisting of thymoglobulin, belatacept, and DBMT. The results were compared with recipients treated with conditioning regimen consisting of Atgam and anti-CD154 mAb, with and without anti-CD8 mAb. Results In 4 consecutive NHP recipients treated with the modified conditioning regimen, homeostatic recovery of CD8+ TEM was delayed until after day 20 and multilineage chimerism was successfully induced. Three of the 4 recipients achieved long-term allograft survival (>728, >540, >449 days) without ongoing maintenance immunosuppression. Posttransplant MLR showed loss of anti-donor CD8+ T cell and CD4+ IFNγ responses with expansion of CD4+FOXP3+ regulatory T cells. However, the late development of DSA in NHP recipients confirms the need for additional anti-B cell depletion with agents, such as rituximab, as has been shown in our clinical trials. Conclusion This study provides proof of principle that induction of mixed chimerism and long-term renal allograft survival without immunosuppression after delayed donor bone marrow transplantation is possible with clinically available reagents. Correspondence author: Tatsuo Kawai, M.D., PhD., White 521, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, E-mail: TKAWAI@mgh.harvard.edu Authorship: K.H. designed and performed the experiments, analyzed the data, and wrote the manuscript. T.O. contributed to the design of experiments and interpretation of results. A.B. performed pre- and posttransplant care of the animals. S.B. designed and performed the experiments and analyzed data. M.M. performed the experiments. I.R., R.N.S., and R.B.C. performed pathological studies. A.B.C designed the study and edited the manuscript. T.K. conceived and directed the study, performed experiments, and wrote the manuscript. Disclosure: The authors have no conflicts of interest to disclose. Funding: The present work was supported in part by Grant 5U19AI102405, part of the NIH NHP Transplantation Tolerance Cooperative Study Group and sponsored by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Canadian Foundation for Innovation. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2EVDmTb