Bone Marrow Cavity Is a Feasible Site for Islet Transplantation in Nonhuman Primates

Abstract

Introduction: The liver, which is currently the only approved site for clinical islet transplantation, presents numerous immunologic and non-immunologic barriers to islet engraftment and survival. The bone marrow cavity represents an attractive alternative site: It avoids liver-specific first-pass metabolism, is easily accessed, and intraosseous delivery has successfully been used as an alternative to intravenous delivery for human bone marrow transplantation. In light of the successful transplantation of islets into the bone marrow of rodents, we hypothesized that the bone marrow could be a feasible site for islet transplantation in nonhuman primates. Methods: Five rhesus macaques were rendered diabetic with streptozotocin. A mean of 13,991 (±3,114) MHC-mismatched islet equivalents per kilogram were transplanted into the bone marrow cavity at five separate sites, including bilateral humeri, bilateral femurs and the iliac crest. Recipients were treated with an immunosuppression regimen that we have previously shown significantly prolongs islet allograft survival: induction therapy with TS1/22, a monoclonal antibody to LFA-1, and belatacept maintenance therapy. Rejection was defined as fasting blood glucose greater than 130mg/dL on two consecutive days. Results: Four of five recipients achieved immediate insulin-independent normoglycemia. The fifth recipient required insulin therapy to maintain normoglycemia; this rate of engraftment with insulin independence is similar to that seen with intraportal islet transplantation. Rejection-free survival for recipients with functional grafts is currently 80, >79, >51 and >29 days. Conclusion: The bone marrow cavity may be a feasible alternative to intraportal islet transplantation and provide an attractive option for clinical islet transplantation.