The Transplant Genomics Research Laboratory focuses on the use of high throughput genomic technologies as a means to understand the immune mechanisms that lead to graft injury and loss, with the aim of identifying gene expression profiles and or genetic variants that may be used to predict those at greatest risk. Data from the laboratory has shown that genetic polymorphisms in key immunoregulatory molecules, specifically chemokines and their receptors, and costimulatory molecules, are associated with altered risk for acute rejection and may influence long-term graft survival in liver and kidney transplant recipients.
Barbara Murphy, MD, is the Principle Investigator of a study, the "Genomics of Chronic Renal Allograft Rejection," which aims to investigate the mechanisms leading to the development of transplant glomerulopathy, chronic arteriopathy funded through the NIH/NIAID Genomics Consortium in Transplantation. The study examines the contribution of the direct and indirect pathways of allorecognition, and the development of de novo donor specific antibodies to this pathologic finding in a large prospective group of renal transplant recipients. The studies is examining the gene expression profile associated with the development of chronic rejection using microarray on protocol biopsies performed over two years following transplantation. In addition, a larger cohort of donor and recipient pairs are being enrolled to identify polymorphic variants of specific immunological genes which confer susceptibility to chronic rejection and the development of donor specific antibodies.
Patients have been enrolled in 5 clinical sites including Mount Sinai, Westmead Hospital Sydney, University Wisconsin – Madison Medical Center, University of Michigan Medical Center, Ann Arbor, and Northwestern Medical Center. The findings of this study will lead to important insights into the pathologic mechanisms mediating chronic allograft loss. Initial finding suggest that differential gene expression on normal 3 month protocol biopsies may be potentially used to immunologically stratify transplant recipients.
Dr. Murphy has also spent many years investigating the ability of MHC derived peptides to modulate the alloimmune response. Specifically she has been investigating the mechanisms of action of MHC class II derived non-polymorphic peptides which have been shown to inhibit the allo- and autoimmune response, and study the potential application of these peptides in animal models.
Dr. Murphy has shown that through binding of the MHC peptide to the outside of the MHC class II molecule, in a manner similar to superantigens, these peptides can qualitatively and quantitatively alter the response to alloantigen. Administration in a fully mismatched islet or vascularized cardiac transplant model leads to significant prolongation of graft survival through the increased production of TGF-β and the generation of peripheral regulatory T cells. The current focus of the lab is to investigate the mechanisms leading to the generation of regulation.
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