2011 - IPITA - Prague


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Parallel session 16 – Open oral presentations Topic: Islet xenotransplantation

16.4 - Islet grafts from neonatal INS-LEA29Y transgenic pigs reverse diabetes in streptozotocin-treated NSG mice

Presenter: L., van Buerck, Munich, Germany
Authors: L. van Buerck, M. Offers, B. Kessler, M. Thormann, J. Postrach, N. Klymiuk, E. Wolf, J. Seissler


Islet grafts from neonatal INS-LEA29Y transgenic pigs reverse diabetes in streptozotocin-treated NSG mice

L. van Buerck1, M. Offers1, B. Kessler2, M. Thormann3, J. Postrach3, N. Klymiuk2, E. Wolf2, J. Seissler1
1 Diabetes Center, Medical Clinic Innenstadt, Ludwig-Maximilian-University of Munich, Munich, Germany; 2 Chair for Molecular Animal Breeding and Biotechnology, Ludwig-Maximilian-University of Munich, Oberschleissheim, Germany; 3 Department of Cardiac Surgery, Ludwig-Maximilian-University of Munich, Munich, Germany

Objective: Facing the limitation of islet transplantation success in treatment of type 1 diabetes by human donor organ shortage and the required intensive immunosuppressive regimen, islet xenografts from a recently generated novel LEA29Y transgenic pig model represent a promising source to overcome these problems. LEA29Y, a high-affinity variant of CTLA4-Ig has already been shown to exhibit immunosuppressive properties.

Methods: Islet-like clusters from neonatal pigs expressing LEA29Y under the control of the porcine insulin promoter or from wild-type pigs were isolated, cultured for 6 days in vitro, and subsequently transplanted under the kidney capsule of streptozotocin-diabetic NOD-scid IL2Rgammanull (NSG) mice. The graft function was assessed by intraperitoneal glucose tolerance testing (ipGTT) after development of normoglycemia. LEA29Y was determined applying immunohistochemical methods and a self-developed ELISA.

Results: Beta cell-specific transgene expression was detectable in neonatal pig pancreas as well as in grafts of murine recipients. Mice of both transplantation groups (TxLEA, Txwt) developed normoglycemia within 3-8 weeks after transplantation without abnormal blood glucose excursions during the ongoing period of examination. Blood glucose levels in the fasting state as well in response to intraperitoneal glucose application were comparable in both, TxLEA and Txwt, and were even slightly diminished as compared to untreated normoglycemic NSG control mice (p<0.01). Determination of graft-derived insulin secretion revealed glucose-induced porcine insulin secretory response to be adequate to compensate for the lacking endogenous insulin secretion. Furthermore, mice transplanted with LEA29Y transgenic islet clusters displayed a glucose-responsive LEA29Y release from the graft in subtherapeutic concentrations.

Conclusions: The present data demonstrate that islet clusters from a newly generated LEA29Y transgenic pig model can reverse diabetes in immunodeficient mice after in vivo maturation towards a metabolically functional endocrine tissue. In ongoing experiments, mice are reconstituted with human PBMCs to elucidate the potential of LEA29Y to inhibit xenogeneic human-anti pig graft rejection.


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