The mission of the Transplant Forum is to improve the quality of life for organ transplant patients and their families by supporting novel research and clinical care programs at Columbia University Irving Medical Center. Please consider making a gift to advance this important work today. Philanthropy is crucial to our ability to carry out ambitious research, which makes the potential impact of your gift enormous. Examples of ongoing research projects include:
Heart Transplant Research
Dr. Farr is studying the potential of organ donation after cardiac death (DCD) to increase the number of viable hearts available for transplantation. In recent years, an increasing number of transplants have resulted from a designation of “cardiac death,” rather than “brain death.” Cardiac death is an ethically and legally appropriate end of life designation applied to patients whose circulatory and respiratory functions have permanently ceased. DCD only occurs after family and caregivers have independently provided consent to the protocol. In New York, DCD donors are not utilized for heart transplantation, although it is used for other types of organ transplant. Preliminary research suggests use of DCD has the potential to significantly expand the number of successful heart transplants in the New York region. This research entails the development of new clinical protocols for how to manage a DCD heart transplant at CUIMC and several other major New York transplant centers.
While the last decade has seen improvements in survival following heart transplant (HT), long-term outcomes remain suboptimal with graft failure being a leading cause of both early and late death. Current immunosuppression is limited by untoward side effects with over 40% of patients developing severe chronic kidney disease by 10-years, a factor that is associated with worse overall outcomes. At the same time, from an immunological perspective, patients continue to experience cellular, humoral (antibody mediated), and chronic rejection with approximately 30% of recipients developing donor specific antibodies (DSA). These antibodies, especially if they are new in onset after transplant, portend a worse outcome with increased risk of cardiac allograft vasculopathy/ graft dysfunction and reduced survival. As such, better immunosuppressive strategies are required that can improve long-term outcomes for the heart, while reducing the morbidity associated with current therapies, in particular calcineurin inhibitors (CNI).
The heart transplant program is participating in a multi-center study of the HeartMate III Left Ventricular Assist System (LVAS). Under the leadership of Yoshifumi Naka, MD, PhD, Columbia has assessed outcomes among advanced-stage heart failure patients receiving the HeartMate III LVAS. Researchers evaluate the device’s ability to provide long-term support, or “destination therapy,” for patients who are not candidates for cardiac transplant. The device will also be evaluated as a short-term, “bridge-to-transplantation” option for patients who are awaiting a viable donor organ.
Heart Pumps as Bridge to Transplantation - Emmanuel Zorn, PhD; Paolo Colombo, MD; Maryjane Farr, MD and Susan Restaino, MD | Adult Transplant Research
The team is studying the way the immune system responds to heart pumps implanted as a bridge to transplant. Installation of a heart pump can cause an immune reaction known as sensitization, which can make it difficult for the patient to match with a heart donor and increases the risk of rejection after transplant. In recent experiments, Drs. Colombo, Farr, Restaino and Zorn identified a subset of white blood cells known as “innate B cells” that appear to be activated in patients receiving heart pumps and may contribute to sensitization. This is an important step toward understanding how the immune system is controlled in heart transplant candidates and will allow physicians to develop and test new approaches for preventing rejection after a transplant.
Dr. Maurer is working to improve diagnosis of cardiac amyloidosis. The amyloidoses are a group of diseases caused by misfolded proteins that deposit in various organs, including the heart, and lead to organ failure. Primary (or AL) amyloidosis is caused by proteins produced in white blood cells, and can cause rapid, multiple organ failure. TTR amyloidosis progresses more slowly, resulting in heart failure and irreversible nerve damage. Both forms, if left untreated, are fatal, and it is vital to quickly distinguish between the two, as prognosis, treatment, and the risk of inheritance differ dramatically by type. TTR amyloidosis, for instance, can be caused by a genetic mutation, in which family members have a fifty percent chance of inheriting the abnormal gene. Dr. Maurer and colleagues lead the nation in offering drug trials for managing TTR amyloidosis, and are developing diagnostic tools that help discriminate between AL and TTR, as well as genetic screening programs to find people with TTR amyloidosis.
Pediatric Heart Transplant Research
Dr. Addonizio is leading several studies in pediatric heart transplant including an NIH-funded multicenter study that addresses how HLA incompatibility, mediators of inflammation, and immunosuppressive drug efficacy influence cardiac transplantation outcomes in pediatric patients; an NIH-funded, multicenter study (CTOTC) with the primary objective to determine the clinical outcomes of sensitized pediatric heart transplant recipients with a positive donor-specific cytotoxicity cross-match and to compare them with outcomes in non-sensitized participants; a retrospective chart review of pediatric patients with hypertrophic obstructive cardiomyopathy who underwent left ventricular septal myomectomy and/or mitral valve replacement; and a retrospective chart review of pediatric patients who underwent heart transplantation to examine the impact of type of immunosuppression therapy and donor recipient EBV status in relation to risk of subsequent PTLD.
Dr. Lee is studying advanced human stem cell techniques, which offer a promising avenue to define the genetic and biological origins of Congenital Heart Disease (CHD). Dr. Lee can convert a CHD patient’s skin cells into actively beating heart cells that can be examined in a petri dish, which allows research as to why a patient’s cardiac muscle is not working. This approach has the potential to individualize patient treatment and is sometimes referred to as “precision medicine”. More broadly, this line of research will examine the genetic mutations that lead to congenital heart defects and how they manifest in the heart at the cellular level.
Dr. Zuckerman’s research interests include pediatric cardiomyopathies, donor and recipient related issues surrounding pediatric heart transplantation, and drug therapies for prevention and treatment of graft rejection following heart transplantation. He currently serves as the local site principal investigator in the Panorama trial evaluating the safety and efficacy of entresto compared with enalapril in pediatric heart failure. He has also been heavily involved in the Clinical Trial in Organ Transplantation in Children (CTOTC) studies examining outcomes and adherence in pediatric heart transplantation, and served as primary author of the consortium’s recently published initial paper.
Kidney and Pancreas Transplant Research
Under the leadership of Dr. David Cohen, Medical Director of CUMC’s Renal and Pancreatic Transplant Program, the kidney transplant team is on the verge of a major breakthrough that would revolutionize renal transplantation and vastly improve quality of life for patients. CUMC is ready to begin clinical trials of induced tolerance in kidney transplant recipients: that is, coaching a patient’s immune system to accept a transplanted kidney without the need for immunosuppression. By combining bone marrow and kidney transplantation from the same live donor, recipients will be able to discontinue all immunosuppression medications without fear of rejection or debilitating side effects. This will dramatically transform the lives of patients and their loved ones.
Dr. Kiryluk is pursuing a new, genome-based approach to match prospective transplant patients with kidney donors. A precise match between patient and donor would potentially reduce the incidence of kidney rejection, improving transplant success rates and outcomes for patients. This work will help lay the foundation for a personalized approach to treating transplant patients.
Dr. Mohan is leading a multidisciplinary team to build a central clinical outcomes research data repository to facilitate clinical care and support robust epidemiological research using big data sciences approaches. This effort will provide insights into treatment strategies that can improve patient centered outcomes for transplant recipients while supporting data linkages to several other clinical research efforts across the transplant initiative.
Safety and Efficacy in Using Eculizumab to Prevent Rejection in Kidney Transplant - Lloyd Ratner, MD, MPH
Dr. Ratner leads a randomized, open-label multicenter trial to determine safety and efficacy of the drug eculizumab in the prevention of antibody mediated rejection (AMR) in living donor kidney transplant recipients requiring desensitization therapy. The purpose of the study is to determine if eculizumab is safe and could be used following desensitization therapy to prevent the condition AMR.
Liver Transplant Research
Liver Transplant without Immunosuppression - Tomoaki Kato, MD, Megan Sykes, MD, and Adam Griesemer, MD
Drs. Kato, Sykes and Griesemer, are developing a method of combining bone marrow and liver transplantation in a large animal model, with the goal of achieving induced tolerance that can be rapidly translated into clinical trials. This technique—a combined liver and bone marrow transplant—could benefit patients with blood diseases that lead to loss of liver function. An example of such a disease is sickle cell anemia. The Columbia Center for Translational Immunology is now working together with Columbia’s liver, adult bone marrow, and pediatric bone marrow transplant teams to plan a trial of combined liver and bone marrow transplantation in this setting. This could be an exciting clinical application for current patients.
Living donation presents a tremendous opportunity to increase the number of organs available for transplantation and save the lives of individuals waiting for transplant surgery. Our scientists and clinicians are working to develop protocols that will make living donation even safer, protecting the health of the donor as they make this amazing gift of life.
Dr. Verna is monitoring the gut microbiome of patients with liver disease, looking for clues to optimize recovery after a transplant. This research is part of a four-year project funded by the National Institute of Diabetes and Digestive and Kidney Diseases to illuminate the role of the intestinal microbiome in recurrent disease following liver transplantation. Chronic liver disease damages the gut barrier and triggers shifts in gut ecology to favor more pathogenic organisms, leading to inflammation and scarring in the liver. To study this disease mechanism, Dr. Verna is examining liver transplant patients, since these patients have an abnormal intestinal microbiome at the time of transplant. Dr. Verna is collecting biological samples from patients before a transplant and in the months and years following the procedure, using 16S rRNA sequencing to track the patients’ digestive microbes. These studies will help establish biomarkers for liver disease recurrence and could provide a guide for how to target specific microbes or metabolic pathways in order to maximize transplant outcomes.
Drs. Sykes and Martinez are investigating a TCR (T cell receptor) sequencing method that has the potential to identify tolerance among transplant recipients. TCR sequencing can identify and trace the specific lymphocytes (immune cells) responsible for acute rejection. Drs. Sykes and Martinez hypothesize that if these cells disappear from a transplant receipient, this could indicate that tolerance has been achieved and that immunosuppression can be decreased. Their goal is to determine if it is safe for patients to slowly reduce and then completely stop immunosuppression drugs.
Pediatric Liver Transplant Research
Drs. Sykes and Griesemer are working to induce tolerance to liver transplants in large animals. This is a necessary step to developing a safe and effective protocol for human transplant patients. Tolerance induction has the potential to fundamentally change our approach to organ transplantation. Although there has been significant improvement in the immunosuppressive drugs that prevent organ rejection among transplant recipients, these medications still cause significant side effects. Inducing tolerance would prevent patients from relying on immunosuppressives, greatly improving long-term outcomes. Tolerance is also an important step in making xenotransplantation—the use of donor organs from other species—a possibility, since the amount of immunosuppression required to avoid rejection of an animal organ in a human patient would be unacceptably high. Xenotransplantation is key to supplementing the limited supply of transplant-ready human organs.
Autoimmune Liver Disease Recurrence in Liver Transplant - Megan Sykes, MD, and Mercedes Martinez, MD
Recurrent disease following liver transplantation is one of the leading causes of organ rejection and health problems for patients with autoimmune liver disease, yet the biological mechanisms that cause recurrence are not well understood. We are now able to identify and follow the specific lymphocytes—blood cells in the immune system—that are responsible for liver rejection. These same lymphocytes are also involved in the liver damage that occurs with recurrent autoimmune liver disease. Drs. Sykes and Martinez are developing techniques to help distinguish between recurrent autoimmune liver disease and organ rejection so that an accurate diagnosis—and the appropriate treatment—can be reached.
Lung Transplant Program
The multi-center NOVEL Lung Trial (Normothermic Ex-Vivo Lung Perfusion as an Assessment of Extended/Marginal Donor Lungs) is under the direction of Principal Investigator, Dr. D'Ovidio. The trial is a study to evaluate the 30-day mortality of patients undergoing lung transplant with lungs from marginal or extended donors treated with ex vivo (outside of the body) lung perfusion versus those undergoing lung transplant with lungs considered transplant suitable. The NOVEL study is using the ex vivo lung perfusion technique to improve donor lung assessment before transplant, and thereby safely increase the number of available lungs for transplant. If the lungs demonstrate a favorable ex vivo evaluation, the lungs will be transplanted into a patient.
Dr. Snoeck is studying lung stem cells and lung regeneration. Dr. Snoeck's lung research recently culminated in a significant breakthrough when he and other scientists at Columbia succeeded in transforming human stem cells into functional lung and airway cells. The findings are a first and have implications for a number of advanced lung diseases.
Pneumonia is major cause of death in patients with lung disease, both before and after lung transplantation. However, as reported by The New York Times and CNN, alarming rates of bacterial resistance to antibiotics are increasingly interfering with our ability to treat even routine pneumonia cases. Thus, Dr. Hook's research program is designed to develop new approaches to treating pneumonia by gaining a better understanding of the way in which bacteria injure the lung. She uses imaging of live mouse and transplant-declined human lungs to visualize and study the interactions between the common yet lethal bacteria, methicillin-resistant Staphylococcus aureus (MRSA), and the cells lining the lung air sacs, where pneumonia occurs. It is her hope that her research will lead to entirely new treatments for lung infection that are not vulnerable to the bacterial mutations that cause resistance.
Dr. D’Ovidio is building a comprehensive repository of biological samples that have the potential to advance knowledge in lung disease and transplantation. The biobank will allow researchers to monitor for biomarkers/indicators of clinical outcomes such as lung function, chronic rejection, or infection. By studying biobank samples, we are in a position to examine the risk factors associated with transplanting certain lungs based on the donor’s genetic background, medical history or exposure to the environment. Using this information, we can develop specialized treatment protocol, tailored to an individual transplant recipient. We can also use information collected from the biobank to determine how a particular patient could respond to immunosuppression.
In addition to dedicated studies looking into new and improved treatments and therapies, Columbia is also leading longitudinal research to study lung transplant outcomes. Under the direction of Dr. Arcasoy, this research includes studying outcomes of patients with advanced lung disease before and after lung transplantation, post-transplant complications, and optimization of post-transplant immunosuppression.
Drs. Arcasoy and Sykes are collaborating to develop new approaches to preventing the rejection of a lung transplant. For several years, Columbia has been working to advance a new technique in which combined organ and bone marrow transplantation induce the immune system to tolerate transplanted organs, preventing rejection without the need for immunosuppressants. Dr. Sykes was instrumental in pioneering this technique, which has been used successfully in kidney patients. Drs. Arcasoy and Sykes are currently working to apply this transplant protocol to lung patients, developing a large animal model to study these protocols.
Columbia Center for Translational Immunology
Dr. Sykes and colleagues were the first to achieve transplant tolerance (to kidney grafts) by using a bone marrow transplant to create a state of “mixed chimerism.” Mixed chimerism refers to a blended immune system, in which a transplant recipient’s body has been educated to recognize a donor organ as “self,” and not reject it. Today, Dr. Sykes and her team are working to extend this approach to other organs and to islet (pancreas) cells. They have developed a new technique involving bone marrow and regulatory T cells that has shown success in a large animal model.
Dr. Sykes’s lab is building on one of its innovations: “personalized immune” mice, which use bone marrow stem cells to recreate a patient’s immune system. The mice provide a model for understanding the immune differences that predispose to type 1 diabetes and the immune responses to transplanted beta cells. The model is also being extended to cancer patients to allow personalized assessment of immunotherapies for cancer.
T Cells in Transplant Recipients - Megan Sykes, MD, Jean Emond, MD, Elizabeth Verna, MD, and Mercedes Martinez, MD
Dr. Sykes’s lab has developed a method of identifying T cells that recognize the donor, as well as a way to track these T cells in transplant recipients. This offers a new way to understand how combined transplantation of bone marrow and kidney re-educates the immune system. Exciting preliminary data suggests the method may provide a remarkably accurate and non-invasive way of diagnosing and perhaps even predicting rejection. Studies are now planned in autoimmune hepatitis/liver transplantation patients in collaboration with Drs. Emond, Verna, and Martinez.
Xenotransplantation Research - Megan Sykes, MD, David Sachs, MD, Kaz Yamada, MD and Adam Griesemer, MD
The Columbia Center for Translational Immunology’s work on xenotransplantation—the use of donor organs from other species—aims to allow the use of pancreatic islets from pigs for transplantation into people. This work will be key to supplementing the limited supply of human organs and islets for transplantation. Dr. Sykes and her team have developed a “humanized” mouse model that has demonstrated two successful approaches to achieving tolerance to pig grafts. Several faculty members have been recruited to take these approaches to the next level, i.e. the pig to primate model: Drs. Griesemer, Yamada, and Sachs.
The Segal Family Biobank collects biological samples which are a crucial resource for translational research. Its mission is to prospectively collect and store samples from recipients of all types of transplants and make these materials available to investigators for clinical research studies. This wealth of available data is critical to our ability to conduct cutting-edge scientific research to further our understanding of organ failure and transplantation.