Projects and Grants

Project Title: Contribution of Toll-like receptor signaling in islet transplantation

KO8 AI071038 NIH/NIAID

Pancreatic islet transplantation is a potential cure for Type I diabetes, a disease which afflicts nearly 2 million persons in the United States, making it the second most common chronic disease in young people. A major challenge is the protection of the marginal islet cell mass. Within a short period after transplantation, inflammatory responses occur in and around the islet grafts, causing early graft failure. Therefore, reducing early inflammation should reduce cell loss and preserve islet cell mass and function. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns. Ligation via TLRs leads to upregulation of pro-inflammatory cytokines and chemokines. Islet cells are among the non-immune cells that express functional TLRs. We hypothesize that pre- and posttransplant events produce intrinsic TLR ligands. Islets detect these ligands locally through TLRs and participate in the regulation of immune responses.

To test this we propose the following Aims:

Aim 1-Determine the impact of Toll-like receptor expression and function on islet cells and their survival. In a syngeneic transplant model we will i) directly assess the role of TLR2 on islet cell survival following prolonged culture; ii) test the relevance of TLR2 expression on parenchymal or bone marrow-derived cells in this process; iii) determine the effect of pre-transplant TLR2 stimulation on the induced adaptive immune response; iv) confirm and define the specificity of TLR activation by analyzing islet-expressed TLR3, TLR4 and TLR9; v) assess mechanisms and potential mediators using a candidate gene analysis approach.

Aim 2-Determine the role of islet cell-associated Toll-like receptor engagement in the alloimmune response and tolerance. In an allogeneic transplant model we will i) test the impact of TLR2 and TLR4 engagement on islet allograft rejection; ii) determine the impact of islet TLR2 and TLR4 expression on costimulatory blockade-mediated permanent islet allograft acceptance.

Our studies will determine the contribution of the innate and adaptive immune response by focusing on TLRs. A detailed understanding of their role in islet recovery and transplantation may provide new therapeutic approaches in islet transplantation without toxic effects on islet cells and without compromising the whole immune system.

Title: Genetic and immune markers to predict HCV recurrence after liver transplantation.

Agency: American Society of transplant surgeons (ASTS) – Pfizer mid-level faculty award Project

Although the results of liver transplantation for non-hepatitis C virus recipients have significantly improved, graft and patient survival has remained unchanged in HCV infected recipients. Our proposal is based on the hypothesis that the susceptibility to recurrence of HCV is modified by inherited genetic variants and that distinct intragraft gene transcripts at the time of transplantation can be identified that can predict recurrence of HCV. We plan to analyze the influence of donor and recipient genotype on the development of HCV recurrence and determine gene expression profiles in implantation liver biopsy samples to identify features that correlate with short and long-term transplant outcome.