Despite more than a decade of work with animal models of islet cell transplantation and numersous clinical trials with both adult and fetal islets, there is still no successful strategy for human islet cell transplantation. The current paradigm predicts that islet graft failure is the result of an immune-mediated regection which is not prevented by potent immunosuppressive drug combinations. We believe that an alternative cause of islet failure after transplantation is the physical disruption of the islets as intact and functioning epithelial cell structures. There is substantiatl evidence that the islet is a complex 3-dimensional structure separating the four different types of endocrine cells around a central core of insulin-producing b cells and integrated spatially aorund a delicate arterial tree. Moreover, animal model evidence indicates that the endocrine function of the islet is uniquely determined by this structure. However, little is known about how the islet's physical structure and dimension is created or maintained. The goal of the present project is to determine the function of extracellular matrix and adhesion receptors in human islets and establish their significance in islet cell transplantation. Our hypothesis is that adhesion moleculars and extracellular matrix determine the growth and development of endocrine cells in the fetal pancreas and maintain the organization, integrity and function of mature adult islets. Thus, one mechanism by which adult islet grafts fail after transplantation is the disruption of t heir normal 3D matrix architecture which results in the progressive endocrine dysfunction observed in the clinical trials. We are comparing the expression and co-localization of adhesion molecules and their ligands in the human fetal and adult pancreas. Specific attention is focused on the 3D structure of the islet and the distribution and morphology of adhesion/matrix ineractions in reference to the arterial system and the polarity of the endocrine cells. We will transplant fetal and adult islet preparations into severe combeind immunodeficient mice and compare and contrast the impact of transplantation on fetal and adult islets with reference to the adhesion/matrix architecture of the islets. Finally, we will use selective inhibitors of adhesion molecule function including monoclonal antibodies and novel peptide analogs to test the impact of disrupting these interactions in vivo after transplantation on both islet morphology and endocrine function. This is an ongoing program of research performed at the NCMIR which has resulted in several publications and continues to be productive.
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