ASTS - Astellas Faculty Development Grant

Erik B. Finger, MD, PhD
University of Minnesota

ASTS - Pfizer Collaborative Scientist Grant

Jonathan S. Bromberg, MD, PhD
University of Maryland School of Medicine

Collaborator - W. Florian Fricke, PhD

Synopsis:  Changes in the taxonomic and functional composition of the human microbiome during immunosuppressive and antimicrobial therapy following transplantation have not been sufficiently characterized. Our hypothesis is that the increased risk for post-transplantation infection results from detrimental changes in the microbial community, resulting from the disturbance of the equilibrium between the human host immune system with the microbiome due to immunosuppressive and antimicrobial therapies. Our goal is to determine the functional setup of the human microbiome, in order to develop prebiotic, probiotic or antibiotic options that could be used as a concomitant treatment in addition to the standard immunosuppressive and antimicrobial therapies.

ASTS - Pfizer Mid Level Faculty Grant

David P. Foley, MD
University of Wisconsin

Synopsis:  A critical mechanism involved in hepatic ischemia reperfusion injury (IRI) is the generation of reactive oxygen species that overwhelm antioxidant defense mechanisms causing cellular injury and death. We have shown that in vitro activation of the Nrf2-antioxidant response element pathway in hepatic stellate cells (HSCs) provides significant protection of hepatocytes from chemical-induced oxidative injury. Our proposal focuses on demonstrating a novel protective role of HSCs on hepatocytes through Nrf2 activation during hepatic IRI. Using transgenic mice that selectively overexpress Nrf2 in a cell-specific manner, we will test our hypothesis in co-culture models of warm and cold IRI, and an in vivo model of warm hepatic IRI. Findings from these studies could lead to the identification of small molecule drugs aimed at activating Nrf2 selectively in HSCs thereby increasing the antioxidant defense required to minimize hepatic IRI. 

ASTS - Genentech Scientist Scholarship

Douglas J. Anderson, MD
Emory University School of Medicine

Synopsis:   The long-term success of renal transplantation is limited by current immunosuppression regimens, which have fallen short in preventing chronic graft loss.  Directed immune therapies that target specific mechanisms of rejection and result in immune tolerance of a transplanted organ without over-suppression are needed.  Repetitive donor-specific alloantigen exposure may allow for creation of a functionally senescent effector T cell repertoire.  We will study whether repetitive donor-specific alloantigen exposure alone or in the presence of various immunosuppressants can lead to reduction in alloreactivity through T cell terminal differentiation and functional exhaustion in non-human primates.

ASTS - Genentech Scientist Scholarship

Synopsis:  Ischemia and reperfusion injury (IRI) related to organ procurement and cold preservation represents one of the most challenging yet understudied problems in clinical liver transplantation. Here, we propose to analyze the emerging function of the "negative" TIM-3– Galectin-9 T cell costimulation pathway in the context of adaptive and innate immune networks, in a clinically relevant mouse model of prolonged hepatic cold ischemia followed by orthotopic liver transplantation (OLT). We hypothesize that crosstalk between TIM-3 on T cells (adaptive arm) and Galectin-9 on macrophages/Kupffer cells (innate arm) regulates pro-inflammatory (pathogenic) and cytoprotective (homeostatic) responses in hepatic IRI cascade in OLT recipients.

ASTS - Fellowship in Transplantation

Synopsis:  Livers retrieved after cardiac death (DCD) are often declined for transplantation because of the high incidence of ischemic type biliary strictures (ITBS). We developed normothermic acellular ex vivo liver perfusion (NEVLP) as a novel preservation technique for the assessment and repair of biliary injury in DCD livers. We propose to compare conventional cold static storage vs. NEVLP in a pig model of DCD liver transplantation. Mechanisms of biliary injury and function will be investigated and predictive markers of ITBS will be determined. The long-term goal of the project is to improve the safety of DCD liver transplantation.

Genentech Presidential Student Mentor Award

Synopsis: An integral part of innate immunity involves the release of many endogenous factors associated with tissue injury. We hypothesize that procurement- and storage-related injury to donor organs results in the release of endogenous innate immune stimulatory molecules that activate graft passenger leukocytes and vascular endothelium; thereby increasing organ immunogenicity and promoting graft rejection. To test this hypothesis, we plan to characterize donor tissues with regards to markers of activation, analyze donor organs for markers of ischemic damage, and determine the immunologic profiles of different donor tissue with respect to cause of death, resuscitation, procurement time, and methods/duration of cold storage.

Genentech Presidential Student Mentor Award

Synopsis: The widespread utilization of lungs donated after cardiac death (DCD) has been hindered by concerns of inferior organ quality. Normothermic ex vivo lung perfusion (EVLP) is an emerging platform for evaluating the quality of potential donor lungs, and may provide some therapeutic effect by flushing pro-oxidative molecules from the vasculature, thereby preserving the integrity of the alveolo-capillary barrier and leading to improved early graft function. We intend to assess the evolution of oxidative stress and tight junction dysfunction in an ex vivo model of DCD lung transplantation, then to investigate the effectiveness of EVLP in reducing or reversing lung injury.

Genentech Presidential Student Mentor Award

Synopsis: Transplantation of plasmid-electroporated primary hepatocytes as therapy in nonobese diabetic mice Allogeneic islet cell transplantation for type 1 diabetes has been successful in achieving insulin independence, but a number of barriers limit the efficacy of this strategy. Recent studies have demonstrated successful delivery of the human insulin transgene in primary hepatocytes and the creation of insulin independent states in diabetic animals. In this study, we investigate: 1) non-viral transduction of mouse hepatocytes with a human insulin transgene; 2) in vitro response of transfected hepatocytes to glucose challenge; 3) in vivo efficacy of transfected hepatocytes following syngeneic transplantation in streptozotocin (STZ) diabetic and autoimmune diabetic nonobese (NOD) mice.

Genentech Presidential Student Mentor Award

Synopsis:  The role of short lived effector cells (SLEC) in the alloimmune response: We are investigating the role of short lived effector cells (SLEC), a population of T cells that develop following viral infection in tandem with memory precursor effector cells (MPEC), in the alloimmune response. These cells are termed “short lived” because of their high apoptotic and low memory potentials. Although some of the signals that drive SLEC over MPEC formation in anti-viral immunity are known, the factors that shape this binary response following allograft transplantation are not yet fully understood. As such, further elucidation of these signals will provide potential means to push allo-specific T cells down a pro-apoptotic pathway and therefore avoid episodes of acute rejection