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Presenter: K., Ishiyama, Duarte, USA
Authors: K. Ishiyama, J. Rawson, A. Oancea, K. Omori, Y. Mullen
Islet allograft tolerance induced by intraportal co-infusion of non-islet pancreatic tissue, mesenchymal stem cells and bone marrow cells
K. Ishiyama, J. Rawson, A. Oancea, K. Omori, Y. Mullen
Beckman Research Institute of the City of Hope , Duarte, USA
Background: We previously demonstrated that allogeneic donor islets, mesenchymal stem cells (MSCs) and BM transplantation into the liver can induce chimerism and donor specific tolerance in rats treated with non-myeloablative preconditioning. Mixed chimerism developed successfully, but some islets failed to function. However, a second set of islets transplanted into chimeric recipients consistently reversed diabetes.
Objective: To eliminate early islet engraftment failure, we examined whether mixed chimerism can be established using non-islet pancreatic tissue, instead of islets, for co-infusion with MSCs and BM cells prior to donor islet transplantation.
Methods: Recipient Wister Furth (WF) rats received a conditioning regimen consisting of anti-lymphocyte serum and 5 Gy total body irradiation, followed by an intraportal co-infusion of Lewis (LEW) non-islet pancreatic tissue, MSCs derived from either BM or adipose tissue, and BM cells and treated with 2-week 15-deoxyspergualin regimen. After 4 to 6 weeks, recipient rats received a streptozotocin injection to induce diabetes before LEW islet transplantation into the liver or under the kidney capsule. Peripheral blood samples were taken for evaluating chimerism and blood glucose was measured after islet transplantation.
Results: The new regimen using non-islet pancreatic tissue successfully induced mixed chimerism with no incidence of GVHD. The percentage of donor phenotype hematopoietic cells in blood was higher in recipients receiving adipose-derived MSCs than those receiving BM-derived MSCs (55.6 ±14% vs. 35.4±10%, respectively) and subsequent islet transplants from LEW rats survived in all chimeric recipients. These grafts promptly reversed diabetes after intraportal infusion of 800 islets or transplantation of 400 LEW islets under the kidney capsule.
Conclusions: Co-infusion of non-islet pancreatic tissue, left-over after islet purification, MSCs derived from either BM or adipose tissue, and BM cells along with a non-myeloablative recipient preconditioning induces stable mixed chimerism and allows for successful islet transplantation performed subsequently into the hepatic, as well as extra-hepatic sites.
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