ASTS - Astellas Faculty Award

Markus Selzner, MD
University of Toronto, Toronto General Hospital

Sponsor:  David R. Grant, MD

Proposal:  Storage, Assessment, and Repair of Liver Grafts for Transplantation Using Ex Vivo Liver Perfusion

ASTS - Pfizer Collaborative Scientist Award

Joseph Leventhal, MD, PhD
Northwestern University

Suzanne Ildstad, MD
University of Louisville

Proposal: Immune monitoring of combined stem cell and kidney transplant recipients

Synopsis:  Renal transplantation is the preferred therapeutic approach for end stage renal disease. However, the chronic use of nonspecific immunosuppressive agents (IS) is costly and has significant toxicities including opportunistic infection, an increased rate of malignancy, nephrotoxicity, and other end organ damage. The induction of donor-specific tolerance would address these limitations. Bone marrow chimerism induces tolerance to transplanted organs and tissues. We have identified a novel tolerogenic bone marrow cell population of CD8+/TCR- facilitating cells (FC) that enhances engraftment of bone marrow in mismatched recipients without causing GVHD. The discovery of FC is an important finding as it opens the door to employing HSCT as a viable cell-based approach for tolerance induction.

We have initiated an FDA and IRB approved clinical trial of FC enriched HSCT and living donor kidney transplantation This Collaborative Scientist proposal will be used to support the prospective immunologic monitoring of pts enrolled in this tolerance trial in order to identify a donor specific immunologic profile that is indicative of tolerance induction, and allow for the rational withdrawal of immunosuppression in patients. 

ASTS - Pfizer Mid Level Faculty Award

Bernd Schroppel, MD
Mount Sinai School of Medicine

Proposal: Genetic and immune markers to predict HCV recurrence after liver trasnplantation

Synopsis:  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.

ASTS - Team Donate Life Award

Michael G. Hughes, Jr., MD
Medical University of South Carolina

Sponor: Kenneth Chavin, MD, PhD

Proposal:  Impact of Race on Pathogenesis of Hepatitis C Viral (HCV) Recurrence Following Liver Transplantation

Synopsis:  HCV recurrence following liver transplant is universal, however rate of disease progression is variable and may be influenced by race.  The purpose of this study is to evaluate the impact of viral and host specific factors in determining magnitude of infection after liver transplant in humans, and how this relates to severity of recurrent disease. To test this, we will determine 1) the impact of HCV genetic variability and receptor density on the amount of virus that infects the liver, 2) how this amount influences rate and severity of recurrence, and 3) the influence of race on the above factors. 

ASTS - *Genentech Laboratories Scientist Scholarship

Na Yin, PhD
Mount Sinai School of Medicine

Sponsor:  Jonathan S. Bromberg, MD, PhD

Proposal:  Lymphangiogenesis in pancreatic islet auto- and alloimmunity

Synopsis:   Lymphangiogenesis occurs during inflammation, although mechanisms regulating it are poorly understood. Our preliminary results demonstrated that lymphatic inhibitors prolonged islet allograft survival. We hypothesize that lymphangiogenesis and the cellular and molecular mechanisms that regulate lymphangiogenesis are major determinants of allorejecting progression. This proposal will explore the roles of lymphangiogenesis and lymphatic production of inflammatory molecules in islet inflammation and alloimmunity. Our project may lead to development of novel approaches for treatment of allotransplantation rejection.

ASTS - *Genentech Laboratories Scientist Scholarship

Joshua Wolf, MD
Johns Hopkins Hospital

Sponsor: Kim M. Olthoff, MD          

Proposal:  Histone deacetylase proteins as a novel therapy for ischemia-reperfusion injury

Synopsis:  Ischemia-reperfusion injury (IRI) is a devastating problem in modern organ transplantation, but it is poorly understood at the molecular level.  Our project aims to investigate the mechanisms underlying IRI and to validate potential therapeutic agents capable of preventing graft damage.  Our preliminary studies in a model for renal IRI have suggested that IRI may be mediated through histone deacetylases (HDACs), a family of transcriptional regulator proteins.  Using a model for IRI in the mouse liver, we will therefore investigate whether HDAC inhibition can lead to a reduction of IRI and an improvement in overall graft survival.

ASTS - NKF Folkert Belzer, MD Research Award

Minh-Tri JP Nguyen, MD CM
McGill University

Sponsor:  Steven Paraskevas, MD, PhD

Proposal:  Can Th17 and regulatory T cells explain the pathophysiology of delayed graft function in kidney transplant recipients? 

Synopsis:  Delayed graft function (DGF) increases risk of acute rejection after kidney transplantation (KTx). Interleukin-6, which is produced in DGF, is critical in directing naive T helper cells differentiation towards T helper 17 (Th17) and away from regulatory T (Treg) cells. We hypothesize there is an increase in Th17 and a decrease in Treg expression in KTx recipients with DGF compared to those without, leading to immunologic consequences. We will test our hypothesis by measuring in both groups expression of Th17, Treg, and related cytokines in blood, urine, kidney biopsy, and kidney preservation fluid, and correlating these results with immunologic events.

ASTS - Fellowship in Transplantation

Andrew Adams, MD, PhD
Massachusetts General Hospital

Sponsor: Christian Larsen, MD, PhD

Proposal: T-cell memory provides a potent barrier to tolerance mechanistic studies and therapeutic strategies

Synopsis:  Transplantation tolerance has remained an elusive objective since it was first described over 50 years ago.  Despite reports of success in rodents, translation to primates and humans has been disappointing.  There is increasing evidence to suggest that an individual’s immune history can influence subsequent responses to an allograft. We have previously shown that T cell memory is a powerful barrier to tolerance induction.  In this study we will systematically evaluate T cell memory as a barrier to tolerance induction.  Specifically, we will define which memory subsets evade tolerance induction, define their recall responses, and investigate signaling pathway inhibitors which may promote their selective deletion.

*Genentech Presidential Student Mentor Award

Jay Lee, BS
University of Michigan

Sponsor: Michael J. Englesbe, MD

Proposal: Sarcopenia and Waitlist Mortality in Liver Transplant Candidates

Synopsis:  MELD is a validated metric currently used to prioritize liver transplants based on predicted waitlist mortality. Despite significant improvements in waitlist survival since the implementation of MELD, there has been increasing momentum to reform policy such that organs are allocated based on survival benefit.  Developing this benefit-based model requires additional metrics to improve survival predictions.  Previous studies have demonstrated that core muscle size is independently correlated with post-transplant mortality. The purpose of this study is to determine whether sarcopenia is independently associated with waitlist survival among liver transplant candidates.  Understanding the role of sarcopenia in waitlist survival has the potential to enhance current predictions of waitlist mortality by capturing the overall health status of the patient, and should strengthen efforts to optimize the allocation of scare organs.

*Genentech Presidential Student Mentor Award

Jeremy J. Song, BS, BA
 University of California, Irvine School of Medicine
 
Sponsor: Joren C. Madsen, MD, D.Phil.
 
Proposal: Induced-pluripotent stem cell-derived cardiomyocytes regenerate autologous cardiac tissue

Synopsis: Autologous tissue-engineered hearts could provide viable tissue grafts needing no immunosuppressive therapy. Adult human fibroblasts can be reprogrammed via ectopic transcription factor expression to pluripotency. Our project discerns whether (1) induced pluripotent stem (iPS) cells be differentiated into cardiomyocytes in significant quantity and purity, (2) iPS-cell derived cardiomyocytes form tissue when seeded onto a 3D-decellularized construct similar (histological, functional, and morphological) to comparable cardiomyocytes. This project is innovative because it proposes a novel technique of regenerating myocardium based upon non-immunogenic patient-specific cells. We anticipate this approach to provide the first milestones for further development of transplantable cardiac tissue grafts

*Genentech Presidential Student Mentor Award

Synopsis: Islet transplantation has emerged as an alternative therapy for Type I diabetes, but shows variable success. While some variables can’t be changed, others could potentially be manipulated by molecular therapeutic approaches, such as minimizing oxidative stress, inflammation, apoptosis, amyloid formation, and immunologic factors potentially improving graft function. Effective delivery of molecular cargos into islets has been problematic due to the complex architecture of the pancreatic islet. In our proposed project, we intend on delivering siRNA molecules into pancreatic islet cells, using gold nanoparticles, to inhibit targeted genes associated with decreased islet graft function through sequence-specific cleavage of the cognate mRNA.

*Genentech Presidential Student Mentor Award

Synopsis:  Hepatic ischemia/reperfusion (I/R) injury is a profound pro-inflammatory response mediated by the innate immune system and a major obstacle for successful liver transplantation. In liver transplantation, dendritic cells (DC) play critical roles in rejection responses; however, their functional importance in I/R injury is understudied. To clarify the role of DC in I/R injury, we will utilize liver warm I/R and orthotropic liver transplantation in Flt3L^–/– mice, which exhibit severe reductions in hepatic CD11c⁺ DC. Ultimately, with enhanced understanding over DC in I/R models, we hope to open novel gateways to potential therapeutic targets which can improve liver graft survival and functional outcome in patients.