ASTS - Astellas Faculty Development Award

Christopher D. Anderson, MD
Washington University of St. Louis

Sponsor:  William C. Chapman, MD

Proposal:  Mechanisms of Increased Cold Ischemia & Reperfusion Injury in Transplanted Steatotic Livers

ASTS - Astellas Faculty Development Award

Linda Cendales, MD
Emory Transplant Center, Emory University

Sponsor:  Allan D. Kirk, MD, PhD

Proposal:  Composite Tissue Transplantation without Steroids or Calcineurin Inhibitors: Alefacept as a Means of Targeting Costimulation Blockade Resistant Rejection

ASTS - Wyeth Collaborative Scientist Award

Seth J. Karp, MD
Beth Israel Deaconess Medical School
Harvard Medical School

Ernest F. Terwilliger, PhD
Beth Israel Deaconess Medical School
Harvard Medical School

Proposal:  Investigation of BMP signaling in liver regeneration using novel viral vectors

Synopsis:  Understanding the molecular basis of liver regeneration may lead to adjunctive treatments for patients requiring transplantation.  Preliminary data in our lab identified a novel, constitutively active signaling pathway which must be inhibited for normal liver regeneration.  To investigate this, we are developing a novel viral delivery system based on adeno-associated virus 8.  Using liver specific promoters, vector-based protein expression can be limited to hepatocytes with no liver toxicity or effect on regeneration.  This system can express genes, and using cre-recombinase, can be modified to delete genes as well.  This work may provide insight into how to modulate liver regeneration, and provide a resource to the transplant community that allows non-toxic, temporally controlled expression or deletion of genes in the liver.

ASTS - Wyeth Mid-Level Faculty Development Award

Dympna Kelly, MD, MCh, FRCSI
Cleveland Clinic Foundation

Proposal:  The role of the Hepatic Artery Buffer Response (HABR) in the Pathophysiology of the Small-for-Size (SFS) Liver Graft

Synopsis:  The SFS syndrome is a significant source of morbidity and mortality following adult living donor liver transplantation. Increased portal vein blood flow is central to the problems following transplantation of partial liver grafts but the precise mechanism of graft injury is unclear. We are studying the SFS liver graft in a porcine model. Our goal is to institute therapeutic measures to improve outcome following transplantation of SFS grafts. The objective of this project is to test the hypothesis that “following transplantation of SFS liver grafts, the normal hepatic artery buffer response (HABR) is superseded by sustained arterial vasoconstriction and de-arterialization of the graft, events triggered by excessive portal vein blood flow”.   

ASTS - Roche Laboratories Scientist Scholarship

Raymond John Lynch, MD, MS
University of Michigan Department of Surgery

Sponsor:  Jeffrey D. Punch, MD

Proposal:  Detection of Alloreactive B Cells in Kidney Transplant Patients

Synopsis:   This project will investigate the place of accommodation, or acquired resistance of donor organs to injury from an intact recipient immune system, in clinical renal transplantation.  We will study the change in frequency of allospecific B cells in the recipient following renal transplantation, and analyze the significance of change in B cell titer as a predictor of acute or chronic rejection.  Expansion of the allospecific B cell compartment without a corresponding rise in alloantibody or clinical evidence of rejection may indicate accommodation in the recipient, and could prompt a reassessment of accommodation’s role in response to allogeneic tissue.   

ASTS - Roche Laboratories Scientist Scholarship

James E. Tong, MD
University of California, San Francisco

Sponsor:  Peter G. Stock, MD, PhD

Proposal:  Effects of Daclizumab on Regulatory T Cells in Pediatric Renal Transplants

Synopsis:  Although great strides have been made to improve short-term outcomes, long-term allograft survival has not shown the same improvement. Current immunosuppression is very effective at preventing acute rejection. However, the long term effects of calcineurin inhibitors play a role in chronic allograft nephropathy. The goal of this research is to identify novel means to promote the survival of regulatory T cells in the age of current immunosuppression. Our hypothesis is that pediatric renal transplant patients after induction and while on immunosuppression will have lower absolute number of regulatory T cells but have a stable if not increased regulatory T cell to effector T cell ratio. We will test our hypothesis by prospectively immune profiling our renal transplant patients by FACS analysis. By promoting the survival of regulatory T cells, we can safely lower immunosuppression which will improve long term kidney allograft survival as well bring us one step closer to tolerance.

ASTS - NKF Folkert Belzer, MD Research Award

Joseph Lillegard,  MD, PhD
Mayo Clinic, Rochester, MN

Sponsor:  Scott L. Nyberg, MD, PhD

Proposal:  Creation of Transgenic Fumarylacetoacetate Hydroloase (FAH) Deficient Porcine Embryos

Synopsis:  The ability to expand human hepatocytes has been a challenging goal for researchers for almost three decades.  Human hepatocytes are highly sought after for drug metabolism testing, the study of the pathobiology of human diseases and more recently in the development of bioartificial liver systems.  A recent report by one of our co-investigators (Grompe et al., Nature Biotechnology, July 2007) demonstrated that human hepatocytes can be expanded to near complete replacement of the livers of Fumarylacetoacetate hydrolase (Fah) deficient mice.  In order to facilitate further scale-up of this fundamental observation, we propose to create Fah deficient pigs using modern techniques of nuclear transfer and cloning.  These FAH deficient pigs will serve as a new large animal model for the fetal transplantation and subsequent large-scale expansion of human hepatocytes.

ASTS - Novartis Fellowship in Transplantation

Alp Sener  MD, PhD
University of Maryland Medical Center

Sponsor:  Benjamin Philosophe, MD, PhD

Proposal:  Role of Alloreactive Memory CD4 T Cells in Transplantation

Synopsis:  Polyclonal antibody immunosuppression during transplantation leads to a progressive and rapid decline in T-cells. If maintenance therapy is not instituted, rejection ensues despite low T-cell counts.  We hypothesize that naïve and memory CD4 T-cells exhibit differential susceptibility to T-cell depletion and that they differ in their efficiency of subsequent reconstitution and functionality.  A novel murine model will be used to examine the subset composition and functional capacities of reconstituted T-cells at various times after T-cell depletion.  Results will reveal fundamental mechanisms for the altered T-cell milieu following induction which may eventually lead to improved strategies for long-term allograft survival.

ASTS Vanguard Prize

Daniel Kreisel, MD, PhD
Washington University in St. Louis                                                       

Synopsis:  Lung grafts are considered to be highly “immunogenic” contributing to markedly worse outcomes after lung transplantation compared to transplantation of other solid organs. Advances in the field of lung transplantation have been hampered by the lack of a physiological mouse model of lung transplantation. We have developed and characterized a vascularized orthotopic single lung transplant model in the mouse, which will allow for the design of mechanistic studies that investigate cellular and molecular aspects of allograft rejection and ischemia reperfusion injury.

ASTS Vanguard Prize

Shimul A. Shah, MD
University of Massachusetts Medical School                                      

Publication: Shah, S.A., Levy, G.A., Greig, P.D., Smith, R., McGilvray, I.D., Lilly, L.B., Girgrah, N., Cattral, M.S. and Grant, D.R.  Reduced Mortality with Right-Lobe Living Donor Compared to Deceased-Donor Liver Transplantation Wehn Analyzed from the Time of Listing.  American Journal of Transplantation, 2007; 7: 998-1002.

Synopsis:  Right lobe living donor liver transplantation (RLDLT) is not yet a fully accepted therapy for patients with end-stage liver failure in the Western hemisphere because of concerns about donor safety and inferior recipient outcomes.  An outcome analysis from the time of listing for all adult patients who were listed for liver transplantation (LT) at our center was performed.  From 2000 to 2006, 1091 patients were listed for LT.  154 patients (LRD; 14%) had suitable live donors and 153 (99%) underwent RLDLT.  Of the remaining patients, 350 underwent deceased donor liver transplant (DDLT); 312 died or dropped off the waiting list; and 275 were still waiting at the time of this analysis.  The LRD group had shorter mean waiting times (6.0 vs. 9.8 months; p<0.001).  Patients in Group 1 had a survival advantage with RLDLT from the time of listing (1-year survival 90% vs. 80%; p<0.001).   This is the first report to document a survival advantage at time of listing for RLDLT over DDLT.

Roche Presidential Student Mentor Award

Henry G. Cheng, BS
David Geffen School of Medicine
University of California Los Angeles

Sponsor:  Gerald S. Lipshutz, MD

Proposal: INDOLEAMINE 2,3-DIOXYGENASE: A Novel Immunosuppressant for Transplantation

Synopsis:  Organ rejection following allogenic transplantation remains a significant problem. Immunosuppressant drugs provide long term acceptance but expose the recipient to infection, malignancy, and atherosclerotic disease. Development of immunosuppressants within the allograft alone has the potential to prevent allogeneic rejection. Data in mice suggest that indoleamine 2,3-dioxygenase (IDO) is an important regulator of T cell activity and prevents allogeneic fetal rejection. We hypothesize that localized overexpression of IDO will prevent allogeneic transplant rejection. By transplanting hearts from C57BL/6 mice expressing the human IDO gene into wildtype Balb/C mice, we will determine if allograft overexpression of human IDO results in allogeneic organ acceptance.

Roche Presidential Student Mentor Award

Denver M. Lough, BS
Georgetown University School of Medicine

Sponsor:  Thomas M. Fishbein MD

Proposal: 16S rRNA Fluorescence in situ Hybridzation of Invading Microorganisms in Small Bowel Allografts of Patients with NOD2 Polymorphisms

Synopsis:  Polymorphisms in the nuclear oligomerization domain 2 (NOD2) have been associated with decreased antimicrobial peptide (AMP) activity per a disconnect in the ileal denderitic-paneth cell augmentation network. AMPs act via this immunomodulation circuit, and when found to be decreased, permit bacterial adhesion/invasion to bowel epithelium. The goal is to evaluate NOD2 associated bacterial dynamics, using 16s rRNA FISH on biopsies collected from small bowel transplant patients, while monitoring luminal AMP levels using ELISAs on parallel effluent specimens. Depicting a clear linearity between NOD2 genotypes, AMP luminal levels and bacterial behavior will further help in developing a mechanism of this defect.

Roche Presidential Student Mentor Award

Juliet Emamaullee, PhD
University of Alberta

Sponsor:  Norman M. Kneteman, MD, MSc, FRCSC

Proposal: The Role of Angiogenic Factors in Epithelioid Hemangioendothelioma

Synopsis:  Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumour of unknown etiology.  The majority of patients present with tumours in the liver, and many of these patients undergo liver transplantation. Given the rare occurrence of this malignancy, randomized trials of traditional cancer treatment options including chemotherapeutic agents and radiotherapy have not been possible. The primary purpose of this study is to characterize the role of VEGF and its receptors in hepatic EHE. If VEGF is highly expressed in most of the samples, it would suggest that an anti-VEGF drug such as bevacizumab should be considered for these patients, particularly as a neoadjuvant therapy in the setting of liver transplantation.

Roche Presidential Student Mentor Award

Ann DeBord Smith, BA
University of Chicago

Sponsor:  Giuliano Testa, MD, FACS

Proposal: Towards an Online Matching Mechanism for Kidney Paired Donation

Synopsis:  I will apply Markov Decision Process (MDP) models to create an online allocation method for kidney paired donation to study optimal allocation policies. A good policy for a kidney paired donation MDP model might allow some, but not all, feasible paired donation matches to proceed to transplantation as soon as they are discovered. This software will be tested using a database generator of simulated donor-recipient pairs to determine the degree of efficacy in matching pairs.