We recently demonstrated that autologous, bone marrow-derived mesenchymal stem cells (MSC) promote allogeneic islet engraftment and survival in a streptozotocin induced, cynomolgus monkey model of diabetes. In this study, we assessed the effect of timing on MSC mediated prolongation of rejection free and overall islet allograft survival. Intrahepatic (IH) islets (4,000 – 15,000 IEQ/kg) were transplanted on postoperative day (POD) 0. Passage 4 (P4) MSC were utilized, wtih 1×10⁶ cells given IH and 2×10⁶ given IV in the following groups: 1) IH islets alone (n=6), 2) IH islets/MSC on POD 0 (n=4), 3) IH islets/MSC on POD 0 + IV infusions of MSC on POD 5, 11, 18 and 28 (n=5) and 4) IH islets alone on POD 0 +IV infusions of MSC on POD 1, 5, 11, 18 and 28 (n=4). Subtherapeutic immune suppression consisted of thymoglobulin (10 mg/kg) on POD -1, 0, 2 and 4; daily FK506 from POD -1 through POD 27-30 and rapamycin from POD 28 through the end of the experiment (target trough levels 8-12 ng/ml). Rejection free survival (RFS) was determined based on elevation in fasting and post-prandial blood glucose levels, in association with decreased fasting c-peptide and increased exogenous insulin requirement. Overall islet survival (OS) was the last POD for which the weekly fasting c-peptide level was >0.3 ng/ml. Median RFS was 43, 29,105 and 68 days, and median OS was 62, 39, 180 and 92 days, for groups 1, 2, 3 and 4, respectively. RFS for group 2 (IH islets/MSC on POD 0) was significantly lower as compared to group 3 (IH islets/MSC+ IV MSC) or group 4 (IH islets alone +IV MSC) at POD 60, 120 and 180. Median OS for group 2 was also significantly lower as compared to group 3 (POD 60) and groups 3 and 4 (POD 120 and 180). These data show that IH co-transplantation of islets/MSC alone is not sufficient to enhance allogeneic islet engraftment and survival. Post-transplant IV infusions of MSC are critical to achieve enhanced RFD and OS. Optimal results are obtained with combined administration of MSC with islets on POD 0 plus post-transplant IV MSC infusion on POD 5, 11, 18 and 28.

CITATION INFORMATION: Kenyon N, Willman M, Han D, Rabassa A, Diaz W, Leeman R, McHenry K, Salomon D, Bartholomew A, Kenyon N, Berman D. Timing of Mesenchymal Stem Cell Infusions Affects Rejection Free and Overall Islet Allograft Survival. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress