Weill Medical College of Cornell University

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Nephrology & Hypertension Research

 

Translational research in transplantation is a major focus of our research efforts. We have resolved signaling requirements of T cells, mechanisms of action of immunosuppressive drugs, mechanisms of post-transplant malignancy, and developed molecular assays for assessing transplant status. We have demonstrated that T cell CD2 antigen is a signaling receptor for antigen presenting cells and resolved a T cell co-stimulation pathway of importance to transplantation (reported in J Exp Med 1990). We discovered a novel mechanism for cancer metastasis (Nature 1999) and identified new treatments that preserve transplant function while blocking tumor progression (Transplantation 2002 and Kidney International 2003). We have developed noninvasive and nucleic acid based assays for the prediction of transplant status and outcome (NEJM 2001 and NEJM 2005). We have contributed to the first ever induction of tolerance to HLA- mismatched kidney transplants (reported in NEJM 2008). Our research in type 1 diabetes has resulted in the first successful human pancreatic islet transplantation in the tri-state area, and in a curative cell therapy for type 1 diabetes (Proc Natl Acad Sci USA 2007).

Transplantation Laboratory

The Transplantation Laboratory, within the Division, has made substantive contributions in the areas of transplant immunology and molecular biology, and has resolved mechanisms of action of immunosuppressive drugs, signaling requirements of T cells, mechanisms of post transplant malignancy, and molecular diagnostics. We are refining gene expression profiles to accurately predict organ transplant status. In our recent studies, we have found that the two major complications affecting all organ transplants, acute rejection and chronic rejection, can be predicted with greater than 95% accuracy with the use of the gene expression panel developed in our laboratory (reported NEJM 2001 and NEJM 2005). One of our major goals is to use the gene expression profiles of transplant patients to reduce drug therapy and minimize or eliminate drug related complications such as life threatening infections or malignancy. Our gene profiling studies should pave the way for the safe induction of transplantation tolerance. In this regard, our molecular studies have already contributed to the first ever induction of tolerance to HLA- mismatched kidney transplants (reported in NEJM 2008).

Diabetes Research Laboratory

The Diabetes Research Laboratory includes Human Islet Isolation Center responsible for the first successful human islet transplantation in the tri-state area. In 2007, we developed a new type of cell therapy, in collaboration with Dr. R. M. Steinman of Rockefeller University, that may cure type 1 diabetes as well as protect the transplanted islets from autoimmune destruction characteristic of type 1 diabetes (reported in Proc Natl Acad Sci USA 2007). We have also developed a novel protocol to improve the function of transplanted islets (Reported in the Journal of the American Society of Nephrology 18: 213-22, 2007).

There are two major challenges to wide spread use of islet transplantation in type 1 diabetic patients. They are: (1) the need for life long immunosuppressive therapy; and (2) the need for a large islet mass (usually islets from 2 pancreata are required to make a patient insulin independent). In collaboration with Dr. R.G. Crystal (Chief of the Division of Pulmonary & Critical Care Medicine in the Department of Medicine at Weill Cornell), we have developed a systemic transforming growth factor beta1 gene therapy that obviates the need for immunosuppressive therapy to protect islet grafts. In collaboration with Dr. K. Manova (MSKCC), we have developed methods to accurately assess islet status using confocal laser microscopy. Importantly, we demonstrated that systemic transforming growth factor beta1 gene therapy can restore self tolerance and facilitate regeneration of beta cell function in a stringent mouse model of type 1 diabetes (Luo et al. Transplantation 2005).

The current barriers to successful clinical islet transplantation include the need for life long immunosuppressive therapy and the need for a large islet mass. Our research discoveries hold considerable promise for overcoming these barriers. Our research results from NIH and JDRF sponsored studies of islet transplantation have been presented at the following National Meetings: American Society of Nephrology 2006, American Transplant Congress 2007, American Diabetes Association 2007.