Basic Science Research Faculty

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• Jose G. Avila, MD, PhD
• Mandy Ford, PhD
• Shiv Gangappa, DVM, PhD
• Neal Iwakoshi, PhD
• Leslie S. Kean, MD, PhD
• Allan D. Kirk, MD, PhD
• Kenneth E. Kokko, MD, PhD
• Christian P. Larsen, MD, D Phil
• 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
• 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 Dr. Avila is an Assistant Professor in the Department of Surgery and the Scientific Director of the Emory Transplant Center (ETC) Cell and Tissue Processing Laboratory. Dr. Avila’s research has been focused on improving organ storage and islet isolation techniques in order to increase islet availability and quality for transplantation. Now, with the aid of an interdisciplinary group conformed by surgeons, basic researchers and technologists he is trying to physiologically and genetically characterize neonatal pig islets (NPI’s) for transplantation into human patients suffering from type I Diabetes Mellitus (T1DM). The recent surge in studies examining xenogeneic sources for islet transplantation in both mouse and non-human primate models demonstrate that the transplant community is entering into a new phase in the effort to utilize porcine donors as a source for islet replacement therapy in the treatment of humans with T1DM. The focus must now include research to obtain critical data in non-human primate models needed to make decisions regarding the design of potential clinical trials using xenogeneic islet tissue in humans. One of our goals is to provide genetic characterization of this tissue, in parallel with islet potency and safety studies currently performed at the ETC. This project uses the expertise of the islet isolation laboratory personnel for the development of procedures to obtain, study and improve NPI for transplantation. In addition, it uses the collaboration of surgeons/researchers for transplantation and follow-up of non-human primates treated with this tissue, using tolerogenic and immunomodulatory protocols currently developed at the ETC. 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 herpes viruses, 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 herpes viruses 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 herpes virus, gamma-herpes virus 68 is genetically related to human gamma-herpes viruses 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. 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 allograft acceptance by an immunocompetent recipient in the absence of immunosuppression, remains an elusive goal of clinical transplantation. The Emory Transplant Center 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. My 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 a costimulation-blockade based immunomodulation strategy Recent Publications return to top

Allan D. Kirk, MD, PhD Professor and Scientific Director, Emory Transplant Center Georgia Research Alliance Eminent Scholar McKelvey Scholar Dr. Kirk's lab is refuting the conventional wisdom that the immune system must be impaired to prevent transplant rejection. When patients undergo an organ transplant procedure, they must take immunosuppressive medications for life to prevent immune rejection of the transplanted organ. These drugs are relatively non-specific and exact significant costs in terms of infectious, malignant and physiological side effects. Thus, transplant patients trade a disease for a condition. Dr. Kirk's work looks at the immune system not as an offensive system void of regulation, but rather an elegant tightly regulated defensive network that provides protective immunity through measured responses to specific threats to homeostasis. It thus must down regulate responses as well as augment them, and is as capable of preventing rejection as it is of causing it. His research had been directed toward understanding the regulatory aspects of immunity and exploiting them to achieve transplant tolerance - a state in which the immune response favors acceptance of an organ rather than rejection. Dr. Kirk's primary goals lie in the transition of therapies from the laboratory into proof of concept clinical trials. His group uses both rodent and non-human primate models of transplantation to model therapies for initial clinical use. Therapies that show promise pre-clinically are investigated in humans under approved renal transplant protocols. His lab is currently investigating several methods for tolerance induction as well as investigating the fundamental signals of injury that trigger immune system activation. 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 interested in the immunologic factors that pose a barrier to acceptance of a transplanted organ such as maintenance of immunologic memory to transplanted organs. 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 also using the relatively new technique of intravital microscopy as a means of investigating the regulation of trafficking of memory lymphocytes into a rejecting organ. In his research on the r egulatory role of interleukin-15 in rejection of skin transplants in a murine model of transplantation, he has found: Interleukin-15 deficiency can lead to prolonged survival of skin grafts with minor antigen mismatches but not fully allogeneic mismatches. Interleukin-15 deficiency leads to an inability of the host animal to maintain immunologic T cell memory. Interleukin-15 deficiency appears to cause a defective alloantibody response with loss of allo-specific antibodies. 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 Carlosand Marguerite Mason Chair, Director of Emory Transplant Center, Vice Chairman of Research-Surgery, and Director of Mason Transplantation Biology Research Center. In recognition of Dr. Larsen's "outstanding contributions and preeminence in the field of transplantation", he was honored as the recipient of the 2007 Thomas E. Starzl Prize in Surgery and Immunology in March 2007 at the University of Pittsburgh. 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 Dr. Mittler’s individual 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, they 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. They 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 Dr. Mittler’s team hopes 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. They further believe that this therapeutic strategy will lead to stronger and more durable immune responses to chronic viral infection. The CD137 receptor (AKA 4-1BB) is an activation inducible member of the Tumor Necrosis Factor Receptor Superfamily (TNFR). A key finding has been that in the mouse, CD137 receptors are preferentially used to activate CD8+ T-cells even though both CD4 and CD8 positive T cells express them. Dr. Mittler’s team collaborating with Drs. Chris Larsen and Tom Pearson was 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. In Drs. Newell and Mittler showed that blockade of the CD137 signaling pathway in mouse small intestine allografts led to graft acceptance. Chris Gilson, a PhD candidate in the Larsen/Pearson lab is now working with Dr Mittler’s group to see whether controlled use of CD137 blocking or activating agents (fusion proteins and mAbs) can replicate the findings of Newell and Mittler in skin allograft transplants. Dr. Mittler’s lab were also 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. Recent Publications return to top

David Neujahr, MD Assistant Professor of Medicine Associate Medical Director, Lung Transplant Dr. Neujahr joined the Transplant Center after finishing a fellowship in Pulmonary diseases at the University of Pennsylvania. Dr. Neujahr is engaged in a longitudinal study of the immune system in patients following lung transplantation. The goals of the research are to identify patients who are at risk of accelerated graft loss through the use of novel immune monitoring strategies. This research takes advantage of the unique opportunity to collect immune cells which have migrated into the lung allograft using fiberoptic bronchoscopy. 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 recently received an NIH KO8 award to study the effects of TGFbeta on the intracellular signaling molecules PPARgamma and Smad3. Using a mouse model of lung transplant, Dr. Ramirez has shown that increased levels of TGFbeta lead to increased Smad3 phosphoralation and subsequent increased in matrix genes responsible for chronic airway remodeling such as seen in bronchiolitis obliterans. Augmentation of PPARgamma using PPARgamma agonists represents a novel way to decrease Smad3 activation and uncouple the link between TGFbeta and chronic rejection. 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 Emory Transplant Center, Dr Rigby primarily studies the immunopathogenisis 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 Emory Transplant Center is on the forefront of better understanding mechanisms of unwanted immunity, primarily using transplant models. As the cellular mechanisms of transplant rejection and autoimmunity likely have significant overlap, progress in both of these fields helps each other. They directly come together in the study of islet cell transplantation as a cure for T1DM. Islet transplantation is a research focus of Dr. Rigby as well as a clinical investigation focus for Emory Transplant Center. Dr. Rigby’s lab uses animal and cellular models to understand the immunopathogenesis of T1DM such as to identify mechanisms that can be (1) interrupted to prevent disease or (2) modified to allow for immune tolerance induction and therefore allow for immunosuppressive-free islet transplantation. Specifically we are using the NOD mouse model, transgenic diabetogenic T cells, and adoptive transfer systems to identify pathways involved with cellular activation of pathogenic T cells. Other studies are using well-defined reagents to interrupt select T cell activation and survival signals to prevent primary disease or disease recurrence after islet transplantation. In addition, Dr. Rigby is assisting in the Transplant Center in the evaluation of patients receiving islet transplants for Type 1 diabetes and studies in non-human primates optimizing islet transplantation with the goal to make islet transplantation more efficacious and generalizable therapy. With these combined efforts we hope to translate “basic” research on diabetes to clinical benefit. 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 The main focus of Dr. Weber’s research 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. A second focus of research is cause(s) of human parathyroid tumors and their functional characteristics. These studies have concentrated on secreted products of human parathyroid tumors including neuropeptides and cytokines and analyses of replication of parathyroid tumors of differing histopathology. Researchers Dr. Weber and Dr. Susan Safley are studying transplantation of endocrine cells, such as pancreatic islets and parathyroid cells. Unlike whole organ transplants, cell transplants may be protected from host immune responses by use of microcapsules as immunoisolation barriers. To block islet xenograft rejection, diabetic NOD mice were given CTLA4-Ig (a soluble fusion protein that blocks B7/CD28 interactions) and/or MRI (a mAb that interferes with CD40/CD154 binding). Microencapsulated islets functioned (bg<250 mg/dl) 13 ± 2 days (n=38); MRI treatment (days 0,2,4, and 6) did not prolong survival (11 ± 1days) (n=8). CTLA4-Ig (every other day for 21 days) extended graft survival to 24 ± 3 days (p<0.002, n=29); MRI + CTLA4-Ig further prolonged function to 57 ± 5 days (p<0.001, n=14). In all groups, graft failure was accompanied by a profuse peritoneal cellular infiltrate of macrophages, neutrophils, eosinophils, CD4 + and CD8 + T cells, suggesting that failure was due to rejection. By contrast, chronic treatment with MR1 + CTLA4-Ig extended graft survival to 111 ± 12 days (p<0.002, n=9), over 200 days in some animals. The profile of PEC from these mice was similar to untransplanted control diabetic NODs and was not characteristic of immunologic rejection. Biopsies of 3 mice with functioning grafts (days 130, 144, and 169 post-transplant) revealed intact microcapsules containing healthy islets with no apparent host cellular reaction. These data show that islet microencapsulation plus costimulatory blockade of host immune responses promotes long-term to indefinite survival of porcine islet xenografts. A second area of research involves studies of secreted products of parathyroid tumors. Parathyroid hormone (PTH) stimulates osteoblasts to produce the proinflammatory cytokine interleukin-6 (IL-6), causing bone resorption. In patients with primary hyperparathyroidism, elevated serum levels of IL-6 normalize after resection of parathyroid tumors. Since IL-6 is also expressed in normal parathyroids and in other endocrine cells (adrenal and islet), we hypothesized that parathyroid tumors might contribute directly to the elevated serum IL-6 levels in patients with hyperparathyroidism. Immunohistochemistry identified IL-6, PTH, and chromogranin-A (an endocrine and neuroendocrine tumor marker) in normal, adenomatous, and hyperplastic parathyroids. By immunofluorescence and confocal microscopy, IL-6 co-localized with PTHand with chromogranin-A in parathyroid cells. All cultured parathyroid tumors secreted IL-6 at levels markedly higher than optimally stimulated peripheral blood mononuclear cells. Supernates from cultured parathyroids stimulated proliferation of an IL-6-dependent cell line, and anti-IL-6 mAb abolished this stimulatory effect. IL-6 mRNA was documented in cultured parathyroid tumors, cultured normal parathyroids, fresh operative parathyroid tumors, and fresh operative normal specimens. In conclusion, these data show that parathyroid tumors and normal parathyroids contain, produce, and secrete IL-6. Our findings present a novel pathway by which human parathyroids may contribute markedly to IL-6 production and elevation of serum IL-6 levels in patients with hyperparathyroidism. The physiologic relevance of IL-6 production by human parathyroids remains to be determined, but IL-6 secretion by parathyroid tumors may contribute to bone loss and to other multi-system complaints observed in these patients. Recent Publications return to top