ASTS - Astellas Faculty Award

Joshua D. Mezrich, MD
University of Wisconsin School of Medicine and Public Health

Sponsor:  Stuart Knechtle, MD

Proposal:  Mechanisms Behind Immunosuppression and Thymic Involution After Exposure to Dioxin

ASTS - Wyeth Collaborative Scientist Award

Allan D. Kirk, MD, PhD
Emory University

Neal N. Iwakoshi, PhD
Emory University

Proposal:  Donor-Specific Memory B cells in Transplantation

Synopsis:  Despite improved control of cellular rejection, no proven therapies exist to prevent donor-specific alloantibody (DSA) formation. Furthermore, the B-cell subsets that produce and sustain DSA production are poorly characterized. This study will investigate the fundamental mechanisms determining the formation of donor-specific memory B cells and plasma cells. We hypothesize that donor-specific memory B-cells have distinct phenotypic and functional signatures that correlate with de novo and anamnestic DSA formation. We will apply novel assays to study donor-specific B cells over time in vivo, quantitating these responses in highly sensitized patients and defining the relationship between the memory B cell repertoire and DSA formation.

ASTS - Wyeth Mid-Level Faculty Development Award

Yuan Zhai, MD, PhD
The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA

Sponor: Jerzy Kupiec-Weglinski, MD, PhD

Proposal:  How Do CD4 T Cells Regulate Innate Immune Responses Against Liver IRI?

Synopsis:  Ischemia and reperfusion injury (IRI) occurs in multiple clinical settings.  As one of the key question in the mechanism of IRI, how CD4 T cells function to facilitate organ inflammation/injury remains to be addressed. We hypothesize that pro-inflammatory effector memory (EM), rather than naïve, CD4 T cells, promote liver innate immune activation without de novo Ag-specific stimulation via the CD154-CD40 pathway.  We will test this hypothesis by: (1) determining the specific CD4 T cell subset and its molecular mechanisms; (2) providing evidence that EM, but not naïve, CD4 T cells functioning in an Ag-non-specific fashion, in liver IRI.

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 - Roche Laboratories Scientist Scholarship

Aaron Ahearn, MD, PhD
University of California, San Francisco

Sponsor:  San Mo-Kang, MD

Proposal:  New Approaches to Understanding Indirect Alloreactivity in Transplantation

Synopsis:   Emerging evidence suggests that CD4+ T cells reacting via the indirect pathway play a major role in acute and chronic rejection.  It is clear that T cells with indirect reactivity can reject allografts in the absence of other T cells or B cells.  The mechanism(s) by which T cells with indirect reactivty damage the allograft are unknown.  We will study this question using a novel T cell receptor transgenic system specifically designed to study indirect and direct alloimmunity, with a focus on the pathogenic mechanisms utilized by the indirect pathway.

ASTS - Roche Laboratories Scientist Scholarship

William H. Kitchens, MD
Emory University

Sponsor:   Christian Larsen, MD

Proposal:  Costimulatory Blockade and the Memory Alloresponse: Defining Barriers to Tolerance Induction

Synopsis:  Costimulatory blockade can successfully induce organ-specific tolerance in rodent transplant systems, but this achievement has not easily translated to more clinically-relevant transplant models in primates.  While the mechanisms underpinning this failure are not fully elucidated, a major contributing factor may be the resistance of memory T cells to tolerance induction by costimulatory blockade.  This proposal seeks to define the factors that are critical for the development of costimulation-independent memory T cell responses that would pose a barrier to tolerance induction.  We will specifically focus on the role of initial T cell precursor frequency as a factor impacting later memory alloresponses.

ASTS - NKF Folkert Belzer, MD Research Award

Thomas Pham, MD
The Ohio State University

Sponsor:  Ginny Bumgardner, MD

Proposal:  Investigating the role of CD8+ T cell and B cell interactions in the regulation of post transplant alloantibody production

Synopsis:  CD8+ T cells, known for their cytotoxic effector mechanisms, appear to negatively regulate antibody production following transplantation. One hypothesis is that CD8+ T cells may directly regulate alloantibody production through the elimination of B cells in lymph nodes. We plan to test this hypothesis by determining if alloreactive CD8-mediated cytotoxic killing of alloprimed B cells occurs in vitro and in vivo. We will also determine the role of CD8+ T cell FasL and/or perforin expression (known cytotoxic effector molecules) on alloantibody production following transplant in a mouse model.

ASTS - Novartis Fellowship in Transplantation

Parsia A. Vagefi, MD
University of California, San Francisco

Sponsor:  Sandy Feng, MD

Proposal:  Simultaneous Liver-Kidney Transplants:  Does a Tolerant Liver Predict a Tolerant Kidney?

Synopsis:  Although advances in immunosuppression have improved allograft survival, their side effects translate into substantial morbidity and mortality for the transplant recipient. As a result, transplantation tolerance remains an overriding goal. There has been a consistent thread of literature describing un-induced, or spontaneous, operational tolerance. Recently, operationally tolerant and non-tolerant liver recipients, as well as kidney recipients, have been characterized with regard to peripheral blood immunophenotypes and gene expression profiles, thereby allowing for predictive profiles of spontaneous tolerance to emerge.  We plan to utilize, in recipients of simultaneous liver-kidney transplants (SLKTx), the tolerance fingerprint established for liver alone and kidney alone transplant recipients. Alignment of liver and kidney tolerance in a subset of SLKTx recipients may not only allow safe immunosuppression reduction, but also lend insight into molecular mechanisms of allograft tolerance, as it has been proposed that the liver affords immunologic protection for the kidney. 

Roche Presidential Student Mentor Award

James R. Cassuto, BS
New York Medical College

Sponsor:  Peter Abt, MD

Proposal: Renal Transplantation for End Stage Renal Disease after a Prior Heart, Liver, or Lung Transplant

Synopsis:  Successful recipients of an extra renal transplant (ERT) are at risk of developing chronic kidney disease with the need for renal replacement therapy, ultimately placing a growing demand on the limited supply of renal allografts.  This project will characterize the risk of waitlist death and potential survival benefit of renal transplantation among patients with a prior ERT.  The risk of waitlist death and transplant benefit will be examined in the context of renal transplant candidates and recipients who do not have an ERT.  Developing an understanding of who can benefit from a renal transplant will allow transplant physicians to make a more informed decision about their patients.

Roche Presidential Student Mentor Award

Hari Keshava, MS
Case Western Reserve University and Cleveland Clinic

Sponsor:  David Mason, MD, PhD

Proposal: Ex Vivo Lung Perfusion for Lung Transplantation: Extending the Donor Pool

Synopsis: In lung transplantation organ demand far exceeds supply resulting in patients dying while awaiting lung transplantation.  Additionally, many donor lungs are not utilized due to perceived poor quality although the methods of organ evaluation are uncertain.  A method of better assessing and even improving the function of these discarded organs might allow their transplantation.  It is our hypothesis that human lungs presently considered non-transplantable by standard criteria can be harvested, evaluated and treated in an Ex-Vivo setting and made suitable for transplantation.  We plan to establish a reliable Ex-Vivo model that can reproducibly evaluate the important physiologic measures of human lung function including oxygenation, ventilation and pulmonary compliance.  This can potentially increase the number of patients being transplanted and ultimately decrease waiting list mortality.

Roche Presidential Student Mentor Award

Smaranda Paunescu
Northwestern University

Sponsor:  Joseph Leventhal, MD

Proposal: Clinical application of regulatory T cells for prevention of allograft rejection

Synopsis: Work in small animal models over the past decade has highlighted the importance of regulatory T cells for the control of immune responses, including allograft rejection.  Our laboratory has demonstrated the ability of adoptively transferred, ex vivo expanded natural regulatory T cells (CD4+ CD25+ foxp3+) to prevent the rejection of cardiac allografts. Our current work is focusing upon human natural regulatory T cells.  We plan to increase this particular cell population by directly isolating and expanding donor specific CD4+CD25+ cells, with the ultimate goal of then re-introducing them into the recipient in order to
induce allograft tolerance.

Roche Presidential Student Mentor Award

Julie Sara Wecsler, AB
University of Southern California

Sponsor:  Linda Sher, MD

Proposal: Creation of a National Database: Liver Transplantation for Metastatic Neuroendocrine Tumors

Synopsis:  Over the past three decades, liver transplant has been performed for a limited number of neuroendocrine tumors with liver metastases. The current organ allocation system does not allow for an exemption for such patients, and in the absence of significant liver disease they are often unable to obtain a transplant. The goal of this project is to analyze the outcomes of transplant according to prognostic factors with the further goal of ultimately establishing a national database and prognostic scale in order to improve upon the disease free survival in these patients.