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Successful induction of tolerance of both islets and kidneys and cure of diabetes following vascularized islet-kidney transplantation in non-human primates

Vimukthi Pathiraja, Joseph Scalea, Masayuki Tasaki, Abraham Matar, Raimon Duran-Struuck, David H. Sachs, Christene Huang, Kazuhiko Yamada

TBRC, Massachusetts General Hospital / Harvard Medical School, Boston, MA, United States

We have previously reported that transplantation (Tx) of prevascularized donor islets as composite Islet-Kidneys (IK) reversed diabetic hyperglycemia in miniature swine, while similar numbers of free islets did not. In order to enhance the IK strategy’s clinical applicability, we attempted to induce tolerance of both islets and kidneys in non-human primates (NHP). Our tolerance strategy included hematopoietic cell transplantation (HCT), 100cGy-Total Body Irradiation, T-cell depletion and 45 days of CyA (ITC).

Methods: IKs were prepared by isolating islets from 70% partial pancreatectomies and injecting them beneath the autologous renal capsule of five rhesus monkey donors (Bwt 4.2-6kg) 3 weeks prior to HCT. Haploidentical HCTwas performed following GCSF mobilization and leukapheresis of the donors and ITCconditioning of the recipients. Three IKs were transplanted to HCTrecipients (Animal 1, 2, 3), one is awaiting Tx and one was used for histology. Animal 1, who was previously tolerant of it’s HCT donor’s kidney, received an IK from the same donor without immunosuppression 211 days post HCT. Animals 2 and 3 received IKs 3 weeks following HCT. IDDM was induced by STZat 80mg/kg IV before IK-Tx.

Results: IK preparation was successful in all monkeys (34000~45000IE). STZinduced IDDM and >15U/day of insulin was required to maintain BS <200mg/dl.Following IK-Tx, all recipients showed stable renal function without evidence of rejection. Insulin treatment (1-5U/day) maintained a BS less than 150mg/dl for 2-3 weeks post IK-Tx in Animals 1,2 and 3. Animals are currently days 139, 189 and 5 from IK-Txs, and FBS are 97, 120 and 77, respectively, without insulin treatment.

Conclusions: We successfully induced tolerance of allogeneic islets as a part of life-supporting IK grafts with HCT. These results demonstrate the feasibility of composite IK-Tx in NHP, with possible clinical applicability for the cure of diabetic nephropathy.