Basic Science Research Faculty

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• Jose G. Avila, MD, PhD
• Linda Cendales, MD
• Mandy Ford, PhD
• Shiv Gangappa, DVM, PhD
• Neal Iwakoshi, PhD
• Leslie S. Kean, MD, PhD
• Allan D. Kirk, MD, PhD
• Stuart J. Knecthle, MD
• Kenneth E. Kokko, MD, PhD
• Christian P. Larsen, MD, D Phil
• Aron E. Lukacher, MD, PhD
• Robert S. Mittler, PhD
• David Neujahr, MD
• Kenneth A. Newell, MD, PhD
• Thomas C. Pearson, MD, D Phil
• Allan Ramirez, MD
• Mark R. Rigby, MD, PhD
• Nicole Turgeon, MD
• Colin J. Weber, MD, Dm, Sci

RESEARCH FACULTY

Jose G. Avila, MD, PhD Assistant Professor Department of Surgery/Division of Transplantation Scientific Director of the Cell and Tissue Processing Laboratory Preparation at Emory of neonatal porcine islets continues according to initial plans. To date we have performed 23 neonatal islet isolations, of which 11 have been transplanted into Rhesus macaques and the remainder (12) have been used for in vitro and in vivo assessment and characterization studies that have helped identify the islets both, from a physiological and a genetic perspective. All preparations have been characterized by flow cytometry and a quantitative PCR analysis of gene expression (for a selected set of primers: Insulin, PDX-1, GAPDH, IGF-1, TGFbeta, VEGF and NEURO D). We have also assessed function through static glucose challenges and following transplant into diabetic NOD-SCID mice. Currently we are using Laser Capture Microscopy techniques in order to identify gene expression in porcine islets that have not undergone the process of islet isolation. The goal is to study gene expression in a “normal” adult pig islet and compare this to neonatal porcine islets after the process of isolation and furthermore after the transplant. This will lead us to the identification of the genes expressed in an efficient adult pig islet to use as a template on what to expect from a transplanted neonatal pig islet, which has not been reported yet. We have great enthusiasm with this project. At Emory, we are also testing a bioreactor cell culture device in a joint effort with Georgia Tech in order to improve the efficiency and reduce risk of contamination of NPI’s cultured during the pre-transplant phase of the process. In addition, we are testing new growth factors like Glial-Cell derived Neurotrophic factor (GDNF) provided to NPI’s during the culture phase in order to improve beta cell mass by the time of transplantation. GDNF has been shown to increase beta cell mass and improve glucose tolerance in mice. This is performed in collaboration with Dr. Shanthi Srinivasan from Internal Medicine at Emory. In addition, we have received a Georgia Research Alliance Award in collaboration with University of Georgia in Athens, for a proposal with Dr. Steven Stice in order to use Porcine Mesenchymal Stem Cells in co-culture with Neonatal Porcine Islets (NPI) as a source of nutrition and immune protection of the NPI’s. The preliminary data of some of this work are being analyzed, and these studies are ongoing at the moment with great enthusiasm by our group. Recent Publications return to top

Linda Cendales, MD Assistant Professor Department of Surgery Emory University School of Medicine and the Atlanta Veteran Affairs Medical Center Early in her career, Dr. Cendales recognized that applying transplant biology to complex composite tissues requiring innervation, integument barrier function, and motor function would involve as of yet un-defined complexities of immunology, reconstructive surgery, orthopedics and surgical technical science that was not represented in modern medicine, that being, composite tissue allotransplantation (CTA). The field of CTA comprises the vascularized transplantation of multiple tissues such as skin, muscle, bone, nerve, and tendon as a functional unit, such as a limb. It is envisioned as a means of replacing non-reconstructable tissue defects, such as those created by traumatic amputations or congenital limb malformations. Dr. Cendales’s work facilitates the development of this emerging medical field. Her team developed a non-human primate model to test new anti-rejection therapy and has initiated trials to characterize the biology of CTA rejection. These studies in CTA in non-human primates are the largest reported in the scientific literature to date. Her group also conceived of and devised the first classification scheme for human CTA rejection and Dr. Cendales presented these findings as the recipient of a Young Investigator Award from the American Transplant Congress in 2003. In addition, she organized the first public international consensus discussions conference in CTA at the Ninth Banff Conference on Allograft Pathology in Spain in 2007 resulting in the Banff CTA 2007 classification for skin allograft pathology,  and will organize the CTA session in the Tenth Banff Conference on Allograft Pathology to be held in Banff in 2009. Dr. Cendales’s goals are to advance this burgeoning emerging discipline from the bench to the bedside in a rigorous academic fashion. Dr. Cendales is the only person in the United States with formal training in both, hand and transplant surgery. She leads the Laboratory of Microsurgery and the CTA program at the Emory Transplant Center. She is an Assistant Professor of Surgery at the Emory School of Medicine and the Atlanta Veteran Affairs Medical Center. Recent Publications return to top

Mandy Ford, PhD A major challenge in the field of organ and tissue transplantation is inhibiting the vigorous immune response orchestrated by donor-specific CD4 + and CD8 + T cells. These cells become activated after recognizing alloantigens and receiving appropriate costimulatory signals, including those transduced through the CD28/B7 and CD40/CD154 pathways. One promising therapy designed to regulate the immune response to donor tissue involves the use of reagents designed to block the costimulatory molecules required for T cell activation. The goal of my research is to use transgenic systems with defined alloantigens to carefully dissect the factors necessary to induce and maintain the state of costimulation blockade-induced tolerance. Specifically, we are focused on four different parameters, which independently impact the fate and function of donor-specific T cells. First, we are investigating the role of donor-reactive CD4 + and CD8 + T cell precursor frequency as a critical factor affecting the degree of T cell proliferation, acquisition of effector function, and requirement for costimulatory signals during allograft rejection or acceptance. Secondly, as a corollary to this work, we are interested in defining the effect of the degree of antigenic exposure of donor-specific T cells on the efficacy of costimulation blockade as a means to induce transplant tolerance. Third, we are examining the impact of stimulation history (i.e. naďve versus memory T cells) on the susceptibility of donor-reactive T cells to costimulation blockade-induced tolerance. Finally, we are interested in studying the impact of TCR affinity for peptide:MHC ligand in the susceptibility of T cells to CD28 and CD154 blockade. Understanding the relative influence of these four parameters on donor-reactive T cell activation and differentiation has broad implications for the development of strategies to inhibit these responses. Recent Publications return to top

Shiv Gangappa, DVM, PhD Assistant Professor Department of Surgery Emory University School of Medicine Dr. Gangappa’s work focuses on the investigation of novel immunotherapeutic strategies for transplantation tolerance in non-human primate and murine models; and mechanisms of viral latency and antiviral immunity in costimulation blockade-induced transplantation tolerance. Most transplant recipients harbor latent infections of several human herpesviruses, which is not surprising given their wide distribution. If the recipient is seronegative for CMV, EBV, HHV-6, or KSHV, the individual is still at risk of infection from donor organs. Infections with any of these herpesviruses can threaten the survival of both the patient and the graft. EBV, KSHV, and HHV-6 have been considered etiologic agents or cofactors for several malignancies. Between 14% and 28% of kidney transplant recipients with a reactivation of KSHV may develop Kaposi’s sarcoma and the disease can be very aggressive in transplant recipients, with a mortality rate of 34% within 3 years of diagnosis. One of the limitations in studying the mechanisms by which herpes viruses affect allograft survival is the lack of a suitable small animal model owing to their species specificity. A murine herpesvirus, gamma-herpesvirus 68 is genetically related to human gamma-herpesviruses and infects laboratory strains of mice, and therefore serves as a good small animal model to study effects of latent infection on transplant tolerance. Dr. Gangappa’s work in this animal model suggests that latent infection in allograft recipients interferes with tolerance induction. The results from this project were featured in the “What’s Hot, What’s New” plenary summary of important new work at the 2007 American Transplant Congress at San Francisco. Ongoing work is aimed at defining mechanisms by which viral and host factors interfere with tolerance induction, and utilize this knowledge to overcome the tolerance resistance barrier and improve strategies for allograft tolerance. Dr. Gangappa is a member of the American Society of Transplantation (AST) and the American Society of Transplant Surgeons (ASTS), and is a reviewer for the journals Microbes and Infection and American Journal of Transplantation. He was awarded the AST Basic Science Faculty Development award for 2007-2009 at the American Transplant Congress in San Francisco in May, 2007. . Recent Publications return to top

Neal Iwakoshi, PhD Assistant Professor Department of Surgery Emory University School of Medicine The unfolded protein response (UPR) is a signaling pathway that is activated when unfolded proteins accumulate in the endoplasmic reticulum (ER). Signals emanating from the ER induce a transcriptional program that enables a cell to survive conditions during which protein folding in the ER is compromised.  Our lab is interested in the molecular basis of this highly coordinated response that it is essential for the folding, processing, export and degradation of all proteins emanating from the ER during stressed and normal conditions. The UPR exists in all eukaryotes and consists of multiple signaling pathways.  Current projects in the lab are focused on the most conserved of these pathways that involves a transmembrane kinase and endoribonuclease called IRE-1 and its transcriptional activator XBP-1. We employ biochemical and genetic tools to study the mechanisms that regulate the UPR within the immune system. To date the most physiologically relevant system to study the UPR has been the highly secretory immunoglobulin secreting plasma cell.  Our studies within the plasma cell have led us to explore molecular events in the ER lumen induced by signals that control B cell differentiation. As our understanding of the molecular details of UPR signaling matures, we are beginning to look to look at other immune cells. Most recently, our studies have begun to examine the UPR in dendritic cells and how this signaling pathway may intersect with the development and function of this critical antigen-presenting cell.  The long-term goal of our research is to establish conceptual basis that will translate into therapeutic manipulation of these responses in the settings of inflammatory and autoimmune diseases and transplantation rejection. Recent Publications return to top

Leslie S. Kean, MD, PhD Fellow and McKelvey Scholar Department of Pediatrics Division of Hematology/Oncology/ Bone Marrow Transplantation Emory University School of Medicine Emory Transplant Center Transplantation tolerance, defined as long-term mutual immunologic acceptance between transplant donor and recipient, in the absence of immunosuppression, remains an elusive goal of clinical transplantation. Dr. Kean's work at the ETC has been at the center of research that has focused on understanding mechanisms leading to transplantation tolerance, with the ultimate goal of translating knowledge of these mechanisms to clinical transplantation. Over the past several years, our group and others have developed strategies targeting the CD40 and CD28 T cell costimulation pathways to control allograft rejection in murine models. By providing costimulation blockade in the peri-transplant period, existing donor-reactive T cells receive “signal one” (supplied by donor cells and antigens) in the absence of “signal two” and are preferentially deleted. This leads to robust, long-term tolerance when normal mice are transplanted under the protection of costimulation blockade. However, when more immunologically complex systems are transplanted with these same techniques, true immunologic tolerance is more difficult to achieve. Dr. Kean's work is focused on four specific questions, all related to transplantation tolerance, and its acquisition in immunologically complex model systems: In a highly immunologically active model of a non-malignant hematologic disease (sickle cell disease) what are the major barriers to the acquisition of transplantation tolerance? How do natural killer cells impact the acquisition of transplantation tolerance, and can control of natural-killer alloreactivity produce transplantation tolerance in otherwise resistant models? In the non-human primate model, what are the major barriers to the acquisition of transplantation tolerance, and can we combine blockade of the costimulation pathway with adoptive cellular therapies to achieve robust donor specific tolerance? During bone marrow transplantation in a rhesus macaque model, what are the barriers to tolerance that result in graft-versus host disease, and can these underlying immune barriers be overcome by costimulation-blockade based immunomodulation strategy? Dr. Kean received her MD/PhD at Emory University in 1999 and completed post-doctoral research, residency and fellowship in Pediatrics and Pediatric Hematology/Oncology in 2005 at Emory University Hospitals and the Aflac Cancer Center and Blood Disorders Service at Children’s Healthcare of Atlanta.  On Faculty since 2005, Dr. Kean currently holds a Burroughs Wellcome Career Award in the Biomedical Sciences, A K08 Clinician Scientist Award from the NIH, and is the Principal Investigator on one of two projects focused on primate transplantation tolerance funded by a NIH U19 Cooperative Group award. She also has funding through the Emory Children’s Center for her novel model of graft-versus-host disease in a non-human primate model, the first of its kind in the world. Recent Publications return to top

Allan D. Kirk, MD, PhD Professor and Scientific Director, Emory Transplant Center Georgia Research Alliance Eminent Scholar McKelvey Scholar When patients receive an organ transplant they must take immunosuppressive medications for life to prevent rejection. These drugs are incompletely effective and cause significant morbidity. Dr. Kirk’s research is directed toward understanding transplant rejection and translating this understanding into less morbid therapies for transplant recipients. His group uses in vitro and animal models to develop transplant strategies and then investigates them in clinical trials. Dr. Kirk has successfully targeted several costimulatory molecules with monoclonal antibodies in primates and is evaluating multiple anti-CD154 approaches pre-clinically. He is interested in the expression of CD154 on platelets and its implications for immune activation and thrombosis. While at the NIH, he initiated several clinical trials using monoclonal or polyclonal antibodies to achieve transient lymphocyte depletion substantially reducing the need for immunosuppression in humans. His group has shown that monocytes play a key role in post-depletional immune responses and are evaluating the signals influencing human monocytes during lymphopenia. He also has determined that memory T-cells are disproportionately spared during depletion in humans and is studying how this affects the post-transplant need for immunosuppression. In addition to developing new therapeutics for use in transplantation, Dr. Kirk has developed several novel means to more precisely monitor transplant recipients. Improved therapeutics and more precise monitoring techniques will facilitate tailor-made immune therapies and improve patient outcomes. Dr. Kirk received his M.D. from Duke University School of Medicine in 1987 and his PhD in immunology from Duke in 1992.  He completed a general surgery residency at Duke in 1995 and a multi-organ transplantation fellowship at the University of Wisconsin in 1995.  He is a Diplomat of the American Board of Surgery and a Fellow of the American College of Surgeons.  He has authored 83 original scientific manuscripts and 50 invited manuscripts on immunological pathways, published in leading scientific peer-reviewed journals. He has developed several novel methods related to immunosuppression resulting in seven patent applications.  He has participated in more than 100 guest professorships, including those at Cambridge, Oxford, Columbia, Duke, Emory, Harvard, Johns Hopkins, Penn, and Yale, and numerous international lectureships.   Recent Publications return to top

Stuart J. Knechtle, MD Professor, Department of Surgery The Emory Clinic and Hospital Surgical Director, Liver Transplantation Clinical Director, Emory Transplant Center Dr. Knechtle joined the Emory Transplant Center as the Liver Transplant Surgical Director in July, 2008.  Dr. Knechtle received his AB from Princeton University in 1978 and his MD from Cornell University Medical College in 1982. He continued his education as a resident in surgery and research fellow in transplant immunology at Duke University and a transplant fellow at the University of Wisconsin. Dr. Knechtle was most recently Ray D. Owen Professor of Transplantation and Director of Liver Transplantation at the University of Wisconsin. Knechtle led a team that performed Wisconsin’s first liver transplant from a living donor and the state’s first combined liver/pancreas transplant.  He is a member of numerous professional societies including American Society of Transplant Surgeons, American Society of Transplantation, The Transplantation Society, Society of University Surgeons, Central Surgical Association, American Surgical Association, and Society of Clinical Surgery. In 1999, Dr. Knechtle was a James IV Association Traveling Fellow. He is on the editorial board of several national academic journals, including the Transplantation, Transplant Immunology, and Annals of Surgery, and is co-editor-in-chief of Transplantation Reviews. Dr. Knechtle’s research focuses on immunology and transplantation tolerance. He is a founder of Renovar, Inc., a biotechnology company specializing in the field of immunology and transplantation. Recent Publications return to top

Kenneth E. Kokko, MD, PhD Assistant Professor Renal Division Emory University School of Medicine Emory University maintains an active collaborative research group in the area of transplant immunobiology.  Dr. Kokko is associated with the transplant immunology laboratory and studies the effects that conventional immunosuppression has on the ability of a subject to maintain protective immunologic memory to antigen presentation. At a basic science level, Dr. Kokko has explored the regulatory role of an inflammatory cytokine, interleukin-15, on the maintenance of T lymphocyte memory to a transplanted organ. In collaboration with Dr. Chris Larsen, Dr. Kokko is studying the effects of immunosuppression on the protective immunity to various viral pathogens such as BK polyoma, influenza and vaccinia. In collaboration with Dr. Kenneth Newell, Dr. Kokko is studying the utility of novel immunologic assays as a predictor of which patients can undergo immunosuppressive reduction safely.  Dr. Kokko serves on the evaluation committee for renal transplantation and is a member of the renal transplant leadership group. Recent Publications return to top

Christian P. Larsen, MD, D Phil Director, Emory Transplant Center Vice Chair for Research – Department of Surgery Carlos and Marguerite Mason Professor of Surgery Department of Surgery Division of Transplantation Emory University School of Medicine Dr. Larsen is an expert in transplantation surgery, immunology and immunotherapy.  With the aid of significant grant funding, his research with Drs. Pearson, Newell and Kirk works to establish true immune tolerance among transplant recipients.  This research strives to free patients from the toxic side effects of daily immunosuppressant medicines and achieve permanent, long-term acceptance of organs.  Areas of primary research focus in his laboratory include: (1) understanding the fundamental mechanisms involved in the T cell response to transplant tissues, specifically the role of costimulatory pathways in T cell activation, and (2) the mechanisms involved in immunologic tolerance to self and transplanted tissues.  Drs. Larsen and Pearson have a strong track record of bringing research to the patient – their research in co-stimulation blockade has been brought from basic research in the early 1990s through the primate center and into highly successful clinical trials in humans led by Emory to apply these strategies to the development of a clinically relevant means to achieving hemotopoietic chimerism as a route to clinical transplantation tolerance. Among his many appointments, Dr. Larsen is Professor and holder of the Carlos and Marguerite Mason Chair, Associate Vice President and Executive Director of Emory Transplant Center, Vice Chairman of Research-Surgery, and Director of Mason Transplantation Biology Research Center. recent Publications return to top

Aron E. Lukacher, MD, PhD Associate Professor Pathology and Laboratory Medicine Division of Anatomic Pathology and Division of Experimental Pathology Emory University School of Medicine Dr. Lukacher's laboratory studies the immune response to infection by oncogenic DNA viruses. They use the well-characterized polyoma virus-mouse model. Polyoma virus, a natural mouse DNA virus, is arguably the most potent experimental oncogenic pathogen known. A major focus of the lab's work is to elucidate mechanisms controlling induction, regulation, and maintenance of effective immunosurveillance against virus-induced neoplasia. Because oncogenic viruses persistently infect their hosts, Dr. Lukacher's lab is also interested in understanding the programming of polyoma-specific memory T cell responses in the setting of chronic encounter with viral antigens. These studies have important implications for development of vaccines to persistently infecting viruses. Most humans are persistently infected by polyomaviruses which can have devastating consequences in immunocompromised individuals. In collaboration with Drs. Larsen and Newell (Dept.of Surgery, Emory University), Dr. Lukacher's lab has developed a kidney transplant mouse model to investigate the pathogenesis of polyomavirus-associated nephropathy, a leading cause of kidney transplant failure. The goal of this lab's research is to develop strategies to manipulate the T cell response to polyoma virus to reverse susceptibility to virus-induced tumorigenesis and prevent kidney transplant rejection. Recent Publications return to top

Robert S. Mittler , PhD Associate Professor Department of Surgery Division of Transplantation and Emory Vaccine Center Emory University School of Medicine The focus of our research program is the study of mouse and human T-cell costimulation pathways that are essential for productive T-cell responses to foreign antigens. In this context, we hope to learn how to artificially regulate immune responses in humans, either to enhance the response in situations of immunodeficiency and tumorigenesis or to selectively diminish the response to organ transplantation or in autoimmune diseases.  Enhancing the immune response. Recently we have focused upon T-cell activation regulated by the PD-1 receptor, a negative regulator of T cell activation, and the 4-1BB receptor an activator of T cells. PD-1 is a member of the CD28 family but unlike the CD28 T cell costimulatory receptor, its function is to counterbalance immune activation by turning it down. By blocking this signaling pathway, in conjunction with anti-4-1BB immunotherapy we hope to enhance the establishment of anti-tumor immunity to refractive, advanced neuroblastoma and Ewing’s sarcoma, two of the most common and fatal childhood cancers. We further believe that this therapeutic strategy will lead to stronger and more durable immune responses to chronic viral infection. Suppressing the immune response. Autoimmune disease and solid organ rejection are examples where immune suppression to self-antigens or alloantigens would be of immense clinical benefit. We, and others have shown that anti-4-1BB monoclonal therapy can either enhance, or suppress immune reactions in vivo. We have shown that anti-4-1BB treatment protects mice from, and reverses established SLE or RA two CD4 T cell and antibody mediated autoimmune diseases. Our recent studies have shown that the decision between immune suppression and immune enhancement depends on the timing of anti-4-1BB treatment. Given during antigen priming, or in the first two days of viral infection anti-4-1BB mAb treatment induces profound suppression of anti-viral immunity. When treatment was delayed 3-4 days anti-4-1BB treatment markedly enhanced anti-viral immunity. Our laboratory has spent the past year trying to understand the cellular and biochemical pathways that direct these two diametrically opposing outcomes. We have made progress by showing that immune suppression is IL-10, TNF, and Fas-dependent. On the cellular level we have found that suppression is mediated through non-antigen dependent CD8 T cells in the host, and independent of antigen-specific T cells. The CD137 receptor (AKA 4-1BB) is an activation inducible member of the Tumor Necrosis Factor Receptor Superfamily (TNFR). A key finding that we made has been that CD137 receptors in the mouse are preferentially used to activate CD8+ T-cells even though both CD4 and CD8 positive T cells express them. In collaboration with Drs. Chris Larsen and Tom Pearson we were also the first to show that administration of monoclonal anti-CD137 antibodies into mice receiving skin or cardiac allografts rejected their grafts much more rapidly than mice injected with a control mAb. Together with Dr. Ken Newell we showed that blockade of the CD137 signaling pathway in mouse small intestine allografts led to graft acceptance. One of our current goals in collaboration with Dr. Chris Larsen’s group is to see whether the use of CD137 blocking fusion proteins can replicate the findings of Newell and Mittler in skin allograft transplants. Together with our colleague Dr. Lieping Chen now at Johns Hopkins SOM we were the first to show that anti-CD137 mAbs proved remarkably effective in completely eradicating established poorly immunogenic tumors in mice. Subsequently Dr. Mittler’s group provided the first long-term comprehensive study that showed that anti-CD137 treatment reversed the course of established SLE and RA in mice and that the treated lupus mice that normally die before one year of age survived for over two years, the normal lifespan of a mouse. Collectively, these studies have led to the U.S. Patent office to award Dr Mittler and his collaborators three U.S. patents for the use of agents that bind to and affect CD137 function. The last of these was awarded in May 2007. During the past six months Sefanie Kunze a German graduate student working as an exchange student in our lab has focused her research on the role of 4-1BB and 4-1BB ligand signaling pathways in a mouse model of Crohn’s Disease (adoptive transfer of CD4+CD45RBhi T cells into C.B-17 SCID mice) an autoimmune inflammatory bowel disease (IBD). Stefanie injected CD4 T cell reconstituted SCID mice with either anti-4-1BB to exert an agonist affect on T cells or 4-1BB-Ig fusion protein that binds to antigen presenting cells that express 4-1BB ligand. Treatment with this reagent is expected to competitively block T cell expressed 4-1BB binding and thus block T cell activation. The mice were examined daily for signs of IBD which include significant weight loss and watery stools. Surprisingly, she found that either form of treatment rapidly induced an inflammatory skin disease and major hair loss in these mice that was first noticed around their eyes and later spread over the entire surface of the mouse. The kinetics of weight loss and diarrhea were likewise accelerated in anti-4-1BB or 4-1BB-Ig injected mice. Taken at face value, Stefanie’s studies suggest that the 4-1BB/4-1BB ligand-signaling pathway may play an important role in maintaining peripheral tolerance and protection from autoimmune reactions. It is a bit too soon to draw any firm conclusions as to why these animals respond to treatment in this way, and one has to wonder if indeed blockade of 4-1BB ligand causes disease, is anti-4-1BB also acting in a blocking fashion? And why is it that neither 4-1BB nor 4-1BB ligand deficient mice develop autoimmune disease? On the other hand, the answer to that question may relate to the highly skewed nature of the immune system of the mice used in this model. Stefanie’s observations were made in SCID mice. These animals have neither T cells other than a limit number of a select phenotype of CD4 T cells adoptively transferred into them and they are completely void of any B cells. At this point we cannot even say whether the skin disease is a result of unchecked adaptive immunity or whether it is solely dependent on an innate immune response. This question and others are now being addressed. Recent Publications return to top

David Neujahr, MD Assistant Professor of Medicine Associate Medical Director, Lung Transplant Dr. David C. Neujahr MD, is a pulmonologist and member of the McKelvey Lung Transplant Program at Emory University.  Dr. Neujahr was recruited to Emory in early 2006 after completing a fellowship program in lung transplantation at the University of Pennsylvania.  Patient outcomes in lung transplantation are quite variable.  Dr. Neujahr’s research is focused on discovery of biomarkers present in lung transplant recipients that are predictive of lung function in the future.  Lung transplant recipients undergo surveillance bronchoscopy at defined time points to assess for silent rejection.  Dr. Neujahr’s group has devised a panel of markers used to screen fluid obtained from the lungs of these recipients.  Current work is aimed at validating the signature of potential rejection in this patient cohort.  Ultimately, these results will be used to define clinical decision making in protocols that are tailored to individual patients. Recent Publications return to top

Kenneth A. Newell , MD, PhD Director, Living Donor Kidney Program Associate Professor Department of Surgery Division of Kidney and Pancreas Transplantation Emory University School of Medicine Basic: Clinical evidence such as inferior graft survival and increased rates of rejection demonstrate that intestinal allografts are uniquely immunogeneic.  Our laboratory has shown that this is at least in part due to a strong immune response mediated by CD8+ T cells.  Importantly, some biologic therapies that inhibit CD4+ T cell function do not impair CD8+ T cell function to the same degree.  We have therefore explored alternative strategies for inhibiting CD8+ T cell function including detailed investigation of several TNF receptor superfamily molecules including CD154, membrane lymphotoxin, 4-1BB, and LIGHT.  These experiments suggest potential targets of intervening in the immune response to intestinal allografts but also provide more basic insights into the behavior of CD8+ T cells that may be applicable to other disease processes such as autoimmunity and immunity to viral infections and tumors. Recently we have expanded our studies to include an examination of tissue specific factors that may contribute to differences in the nature of the immune response to different organs.  The intestine posses a unique immunologic microenvironment which includes organized secondary lymphoid tissues, specialized immune cell populations, and unique chemokines and integrins to regulate cell trafficking.  Our data demonstrate that the secondary lymphoid organs within the transplanted intestine contribute to the process of intestinal allograft rejection and may contribute to the unique immunogenicity of transplanted intestines. In collaboration with Drs. Christian Larsen and Aron Lukacher we have undertaken studies designed to understand the immune response to polyoma BK virus (BKV) following transplantation.  BKV is a common, usually asymptomatic virus that persists in the renal tubular cells of healthy individuals.  Over the last decade BKV has emerged as a major pathogen leading to dysfunction and failure of transplanted kidneys.  However, little is understood about the mechanisms responsible for the control of BKV following renal transplantation.  Making use of unique microsurgical models in mice and immunologic reagents available through the ETC we have submitted an R01 application to the NIH to further investigate BKV-induced nephropathy and evaluate new therapeutic approaches. Clinical:  Outcomes of transplantation have continued to improve dramatically over the last three decades.  This is at least in part due to the development of more and better immunosuppressive agents.  However, the long-term reliance upon drugs that globally suppress the immune system is associated with numerous deleterious side effects.  For this reason, immunosuppressive drug minimization or withdrawal is now an important focus of the transplant community.  Two NIH funded projects seek to address this issue.  In the first funded project we are studying patients who have maintained excellent graft function despite no longer taking immunosuppressive drugs.  This small cohort is recruited from around the world for the purpose of gathering patient data and clinical material to evaluate potential assays predictive of “tolerance”.  The results obtained will be compared to several other groups of transplant recipients.  A second set of NIH-sponsored trials is intended to develop and validate assays for the purpose of guiding decisions about immunosuppessive drug management.  This project is a collaboration among investigators at the Cleveland Clinic, Case Western Reserve, the University of Manitoba, Brigham and Womens’ Hospital (Harvard), the University of California San Francisco, Yale University, and Emory University.  It is comprised of a number of sub-studies aimed at developing assays to monitor both the cellular and humoral response to organ allografts and then to use these assays prospectively to manage immunosuppressive medications following kidney, heart, and lung transplantation. A second major factor contributing to the dysfunction and premature loss of transplanted kidneys is the continued dependence upon nephrotoxic immunosuppressive drugs to prevent rejection.  In an investigator-initiated single center study we will examine the potential of efalizumab, an antibody specific for LFA-1 which has been shown to be immunosuppressive and is FDA approved for the treatment of psoriasis, to replace nephrotoxic calcineurin inhibitors following transplantation.  This study will also make use of new strategies to monitor the immune response following transplantation that are under development at the ETC. Recent Publications return to top

Thomas C. Pearson , MD, D Phil Chief, Kidney Transplantation Livingston Professor of Surgery Department of Surgery Division of Transplantation Emory University School of Medicine T cells play a central and critical role in the rejection of transplanted organs.  Dr. Pearson’s research has focused on better understanding the critical factors for T cell activation and function and the development of novel strategies to block the rejection response.  These investigations have involved the development and assessment of novel immunomygelatory strategies in rodent models and pertinent pre-clinical testing in non-human primates.  These investigations, on the whole of the costimulatory pathways and the alloimmune response, have the ultimate goal of developing a clinically relevant strategy to induce permanent long-term tolerance to transplanted organs in humans. Recent Publications return to top

Allan Ramirez, MD Assistant Professor of Medicine Dr. Ramirez conducts research that centers on chronic rejection after lung transplantation, which is the major limitation to long-term survival. Chronic rejection manifests as a progressive, fibrotic disorder of small airways called obliterative bronchiolitis (OB). The factors that initiate and maintain this process are poorly understood. However, strategies to further suppress immune responses in OB have been largely unsuccessful, suggesting that other processes belie OB. Using an animal model of experimental OB, Dr. Ramirez’ research has shown that the molecule Transforming Growth Factor-beta (TGFbeta) and its second messenger Smad3 play a critical role in fibroproliferative process of this disease. In studies of fibroblasts in cell culture, Smad3 is required for these cells to transform into myofibroblasts which then produce the excess amounts of connective tissue matrices that eventually become deposited in the airways of transplanted lungs with OB. Thus, the focus of Dr. Ramirez’ research is in identifying other pathways and molecules that modulate the actions of Smad3 in the fibroblast. The findings from these studies have demonstrated that:  (1) perturbations in the oxidation state of the cysteine/cystine redox couple can lead to activation of Smad3 in the absence of other stimuli and (2) the connective tissue molecules that obliterate the airway serve to stimulate Smad3 activity in the fibroblasts that produced them, further amplifying and perpetuating the fibrotic process. The search for mediators to counteract the activity of Smad3 has led Dr. Ramirez to the study of several members of the family of nuclear hormone receptors that, when activated, can prevent the elaboration of extracellular matrices in fibroblasts, all through the inhibition of Smad3. It is hoped that this research will lead to the identification of novel targets for the treatment of this otherwise incurable disease. Recent Publications return to top

Mark R. Rigby, MD, PhD Mark R. Rigby, MD, PhD Assistant Professor, Departments of Pediatrics and Surgery McKelvey Scholar, Emory Transplant Center Emory University School of Medicine Director of Research, Critical Care Medicine Children’s Healthcare of Atlanta  As an investigator at the ETC, Dr. Rigby primarily studies the immunopathogenesis and prevention of Type 1 diabetes mellitus. Type 1 diabetes mellitus is an autoimmune disease which targets the destruction of the pancreatic beta cells. The ETC is on the forefront of better understanding of mechanisms of unwanted immunity, primarily using transplant models. As the cellular mechanisms of transplant rejection and autoimmunity likely have significant overlap, progress in each of these fields helps the other. Dr. Rigby’s investigations span from studies in animal models of T1DM and islet transplantation to human investigations of T1DM.  In studies supported by the American Diabetes Association, Dr. Rigby and his team are working to understand how drugs that prevent disease dampen the effect of harmful disease-causing cells, while encouraging the growth of protective, regulatory cells.  And from a recently awarded grant from the American Society of Transplantation/Wyeth Basic Science Faculty Development Award, he will be investigating the immune barriers in islet transplantation in murine models of diabetes. In addition, Dr. Rigby assists in the evaluation of patients receiving islet transplants for Type 1 diabetes to better understand the immune response in human islet transplantation. Dr. Rigby is the PI of a clinical trial that recently received funding from the Juvenile Diabetes Research Foundation and Genentech. In the BRiTE trial (for beta cell rescue in T1DM with efalizumab), ETC and other Emory Investigators be conducting a 5 year single center randomized trial to determine if efalizumab (which interferes with T cell activation and trafficking) can stabilize, or hopefully reverse, T1DM. Through these combined basic and clinical studies, the ETC will be on the leading edge of understanding, developing and trialing therapies to reverse and cure T1DM. In the past year, Dr. Rigby has been first/primary author of over 8 abstracts presented at international conferences, including the American Transplant Society, American Diabetes Association, Keystone Symposium on Immune Tolerance in Autoimmunity and Transplantation, and the Society of Critical Care Medicine, and authored or co-authored 8 peer reviewed manuscripts. He was a featured researcher in the American Diabetes Association “Diabetes Forecast” Magazine (Spring 2008). Dr. Rigby also has been involved with improving pediatric organ donation and serves as the physician liaison between LifeLink of Georgia and Children’s Healthcare of Atlanta/Egleston, has assisted in the development the “organ donation after cardiac death” policy at CHOA (allowing maintenance of UNOS accreditation), and has been a physician leader with the CHOA/Emory Pediatric Transplant Collaborative. Dr. Rigby is involved in many facets of outreach, having been invited to lecture on pediatric organ donation (Atlanta Organ Donation Collaborative, Ethics Grand Rounds Memorial Hospital (Savannah), Noon conference Candler Hospital (Savannah) and given community-based talks on his ETC research progress (American Diabetes Association Pinnacle Society Meeting (February) and ADA/Atlanta’s Kickoff for their annual “Step out to walk to fight diabetes” event).   Recent Publications return to top

Nicole Turgeon, MD Assistant Professor of Surgery Dr. Turgeon is an Assistant Professor in the Department of Surgery.  Her clinical and research interests are in adult and pediatric renal transplantation, pancreatic transplantation, laproscopic liver donor nephrectomy, humoral rejection, and outcomes analysis of transplant recipients.  Dr. Turgeon currently has an IRB-approved protocol for sickle cell anemia and renal transplantation and a protocol in the final stages of the IRB related to the safety and efficacy of bariatric surgery in ESRD patients.  The goal of this study is to increase access for obese patients to renal transplantation provided the procedure is safe. Recent Publications return to top

Colin J. Weber, MD, Dm, Sci William McGarity Professor of Surgery Department of Surgery General and Endocrine Surgery Emory University School of Medicine Dr. Weber’s research focus is pancreatic islet transplantation.  The long-term goal is to develop techniques for safe and durable islet cell replacement for large numbers of patients with insulin dependent diabetes mellitus.  For the past several years, this research has concentrated on the use of xenogeneic tissues as sources of donor islets and microencapsulation plus selective immune modulation of hosts as the means to accomplish cross species islet graft survival.  Working with Dr. Susan Safley, Dr. Weber and Dr. Safley have focused on the NOD mouse which develops diabetes spontaneously in a manner quite similar to type I diabetes in patients.  They have found that spontaneously diabetic NOD recipients reject both isologous, allogeneic, and xenogeneic islets very rapidly, but that microencapsulation of these islets prolongs their survival dramatically.  In addition, Dr. Safley and Dr. Weber have learned that the NOD immunologic response to allogeneic and xenogeneic islets is primarily orchestrated by the host NOD mouse CD4+ T-cell.  Interference with the activation of CD4+ T-cells by the imposition of co-stimulatory blockade agents given to recipients of encapsulated porcine islet xenografts dramatically prolongs their survival to >1 and ˝ years.  In addition in the past year, Drs. Weber and Safley have developed and improved formulation of microcapsules which is both more immuno-protective and durable allowing the long term application of this technique to islet transplantation.  The results of these studies have culminated in a research proposal to test these concepts in diabetic non-human primates in the coming year.  Furthermore, Drs. Weber and Safley are studying a humanized Scid mouse with diabetes which can receive both porcine and human islets and human peripheral blood mononuclear cells PVMs in order to assess human immune reactions responses to islet grafts in vivo.  Recent Publications return to top