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 one diabetes has resulted in the first successful human pancreatic islet transplantation in the tri-state area, and in a curative cell therapy for type one diabetes (Proc Natl Acad Sci USA 2007).
The Transplantation Laboratory, within the Division of Nephrology and Hypertension, 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).
The Diabetes Research Laboratory includes the 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 one diabetes, as well as protect the transplanted islets from autoimmune destruction characteristic of type one 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 widespread use of islet transplantation in type one diabetic patients. They are: the need for lifelong immunosuppressive therapy, and 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 and Critical Care Medicine in the Department of Medicine at Weill Cornell Medicine), 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, and American Diabetes Association 2007.
Principal Investigator: Mary E. Choi, M.D.
Research Interests: Molecular and cellular mechanisms of tissue injury and fibrosis, TGF-β1, cell signaling pathways in the kidney
Research in the Choi Laboratory centers on understanding the cellular and molecular mechanisms of tissue inflammation and injury, including the kidney, lung, and vasculature, in the pathogenesis of acute and chronic diseases. Our work has focused on examining the mechanisms of signal transduction by Transforming Growth Factor-beta1 (TGF-β1), a pleiotropic cytokine and key mediator of tissue injury response and kidney fibrosis. We have extensively examined how TGF-β1 effects are mediated by the distinct TGF-β receptors via activation of intracellular signaling molecules downstream to the receptors in a cell-specific manner to regulate cellular responses in renal cells. Investigations in the laboratory have included (1) cloning and characterization of the cell surface receptors, and identification of novel interacting proteins that are involved in TGF-β1 signal transduction, (2) delineating the downstream intracellular signal transducing pathways that mediate TGF-β1 signals, in particular, the role of the mitogen-activated protein kinase (MAPK) pathways, and (3) the cellular and molecular regulation of TGF-β1 induction of cytoprotectants, such as heme oxygenase-1 (HO-1) and carbon monoxide (CO). We are currently investigating novel mechanisms of the regulation and function of autophagy, inflammasomes and necroptosis in models of organ injury, including the kidney, lung and heart. In collaboration with investigators at Weill Cornell Medicine including Dr. Augustine Choi (Professor, Division of Pulmonary & Critical Care Medicine), Dr. Jeffrey Laurence (Professor, Division of Hematology & Medical Oncology), Dr. Marshall Glesby (Professor, Division of Infectious Diseases), Dr. Lorraine Gudas (Chairman and Professor of Pharmacology), and Dr. Oleh Akchurin (Assistant Professor of Pediatrics, Division of Pediatric Nephrology), we are also studying mechanisms of sepsis, acute and chronic lung injury, HIV/antiretroviral therapy-related cardiac and kidney fibrosis, and juvenile chronic kidney disease. The ultimate goal of our research is to identify novel therapeutic targets that will provide cytoprotection against tissue injury in progressive kidney diseases.
The Division of Nephrology and Hypertension has ongoing studies that are actively enrolling for recruitment. Our innovative research has enabled us to develop and better understand diseases affecting the kidney and renal systems, and alternative non-invasive ways to detect allograft dysfunction. Under the direction of Dr. Manikkam Suthanthiran, the division continues to grow and expand its research, and make significant scientific contributions to the medical world.
We participate in research studies involving the following conditions/diseases: