BIDMC's Transplant Research Center and its principal investigators in the departments of surgery and medicine have national and international reputations for excellence and innovation. The center attracts students, fellows and post-doctoral individuals from around the world. In total, there are over 70 investigators in the Transplant Research Center, which is funded by more than $11 million in grants. Investigators engaged in bench research study the chemical and molecular make-up of cells and tissues for clues about organ rejection and tolerance. Their discoveries become the foundation for clinical research here and around the world.
- Terry B. Strom, MD - Scientific Co-Director, Transplant Research Center
- Laurence A. Turka, MD - Scientific Co-Director, Transplant Research Center
- Nezam H. Afdhal, MD
- Robyn Chudzinski, PharmD
- Michael P. Curry, MD
- Christiane J. Ferran, MD, PhD
- Alexander Goldfarb, MD
- Elzbieta Kaczmarek, PhD
- Maria Koulmanda, PhD
- Gerond Lake-Bakaar, MD
- Didier Mandelbrot, MD
- Anthony P. Monaco, MD
- Leo E. Otterbein, PhD
- Martha Pavlakis, MD
- Simon C. Robson, MD, PhD
- Christin Rogers, PharmD
- James R. Rodrigue, PhD
- Michael T. Wong, MD
The Challenge: Organ Rejection
Transplant patients and physicians face a significant challenge: organ rejection. Our bodies' immune systems are naturally designed to do battle with "foreign invaders." Under normal circumstances, this system is highly effective, protecting us from viruses, bacteria and other infections. However, our immune systems are not as successful at differentiating between dangerous foreign bodies (for instance, bacterial infections) and beneficial intruders (such as a new kidney, liver or pancreas). For organ transplant patients, the normally protective immune response can threaten the longevity and function of the transplanted organ.
Currently, organ transplant patients must take immunosuppressive or anti-rejection medication to prevent the immune system from fighting against the new, transplanted organ. However, over the long-term, these drugs pose a number of risks, and side effects that are particularly devastating to children.
The Mission: Prevent Rejection, Improve Function
Scientists in the Transplant Research Center are working to:
- Develop new methods to prevent rejection
- Develop new methods to diagnose rejection before injury to the transplant
- Improve the function of organs after transplantation
- Reduce the number of medications patients must take to prevent rejection, including reducing steroid use
- Minimize the side effects of therapy
- Create immune tolerance to the transplant to totally eliminate the need for use of immunosuppressive medications
The center's basic or bench research is directed toward a broader understanding about transplant science and immunology (the body's ability to accept or reject foreign tissue), and how medicines can protect and maximize donor organ function and endurance. We are leaders in one) developing new approaches to overcome organ rejection without the use of highly toxic immunosuppressive drugs, and two) diagnosing early rejection and enabling application of medication before the transplant is damaged.
Principal Areas of Investigation
The interests of the research group include immune tolerance and T-cell biology, cytoprotection (the role of protective genes in transplantation), molecular diagnostics, xenotransplantation, liver and beta cell regeneration, vascular biology, and bioinformatics, as well as a number of subspecialties within these key areas.
Immune Tolerance and T-Cell Biology
Immune tolerance refers to the ability of the immune system to accept or tolerate new organs without taking life-long medications. By creating tolerance, researchers hope to ensure long-term transplant function without life-long drug therapy (which carries a number of risks). Scientists investigate the T-lymphocyte cells, or T cells, which are among the body's key infection-fighting cells. Normally T cells circulate through the blood in a resting or naïve state. When they encounter a foreign invader (such as a virus or bacteria) or foreign tissue (a transplanted organ), they receive a chemical signal to attack and destroy the "intruder." Researchers are working to understand this signal - how is it triggered, how can it be disarmed, and how can the T cell be disabled against (or help protect) the donor transplant (to maximize organ function), while remaining vigilant and ready to destroy truly harmful microbes and other infectious agents that enter the body.
BIDMC scientists are leading the way in refining immunosuppressive protocols, or treatment guidelines, to target T cells. They are learning how to train T cells to protect, rather than attack, transplanted organs. They are studying a new combination of immunosuppressive drugs, some of which have been developed in the Transplant Research Center laboratory, called "power mix." Administered for a very short time after transplant, this power mix has been shown to prevent islet cell rejection in monkeys. Islet cells are the insulin producing cells in the pancreas that are deficient in people who have diabetes. Short-term power mix therapy has proven useful in permanently restoring normal blood sugar level and tolerance to islet cells in a mouse model of juvenile diabetes. In a parallel study this same team has determined that a short course of treatment with alpha1 anti-trypsin, a human protein that is normally produced in response to inflammation, is also curative in this model of juvenile diabetes. These studies are paving the way for clinical trials in the near future for patients with diabetes. The power mix also has exciting potential for other autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis.
Another area of T-cell investigation involves a better use of anti-lymphocyte antibodies, to reduce the number of aggressive T cells in the immune system, in combination with donor bone marrow cells. Patients undergoing a kidney transplant, for example, would receive anti-lymphocyte antibodies to knock out the aggressive T-cells, in combination with the kidney donor's bone marrow. This approach has shown great promise in improving organ tolerance.
Cyto or "cell" protection is another significant research area and has to do with protecting the graft, or donor organ, from damage. Scientists examine a process called apoptosis, or programmed cell death. Every cell in our body comes equipped with a unique life-cycle program. Cells survive and thrive until they are no longer useful and then they automatically die. Scientists are looking for the switch: What turns on the death program, and how do cells disappear without notice? With cancer, this orderly process goes haywire, allowing cancer cells to grow unchecked into tumors. In transplanted organs, researchers look to turn off the death program and turn on the survival signal, to keep the organ vital, functioning and less vulnerable to injury.
Researchers also study gene therapy to help protect and fortify the cells in the transplanted organ. Genes, located within the nucleus of each cell, contain our unique hereditary information, a personal blueprint, which is passed from cell to cell. The Transplant Research Center has succeeded in identifying protective genes that have proved useful in fortifying the transplanted organ, helping to prevent chronic rejection and increasing graft survival.
Believe it or not, scientists at BIDMC are also testing carbon monoxide as a cytoprotection agent. Our researchers have learned that the toxic gas found in auto exhaust or faulty heating systems can help prevent the inflammatory responses (swelling, pain and an indication that rejection is underway) that often develop after transplantation. Although inflammation is another of the body's normal defense mechanisms, it can put a transplanted organ at great risk because it can damage the blood vessels that supply the transplanted grafts. Researchers discovered that the mitochondria found inside the cells - essentially the cells' molecular engines - react to low levels of carbon monoxide by releasing chemical signals that reduce or shut down the body's inflammatory response. The gas helps relax arteries and veins so blood can continue to flow and nourish the transplanted organ.
Experiments have also shown that carbon monoxide can prevent the delay in kidney function that sometimes occurs after transplantation. This delay is attributed, in part, to how the organ must be preserved once it is removed from the donor.
Molecular diagnostics examines how proteins and genes interact within a cell, and captures this information as a "molecular signature." Researchers study these gene and protein patterns for early warning signs that predict the likelihood of organ rejection or tolerance. The goal is to disarm the T-cell attackers before the body's immune system can mount a defense and destroy the transplanted organ, thereby short-circuiting the rejection process before it even begins.
Xenotransplantation, or transplanting organs and tissues from one species, such as pig heart valves, into a different species, such as humans, could one day help expand the number of solid organs available for transplantation. The familiar hurdle, organ rejection, is even more ferocious with cross-species transplantation. T cells in the body's immune system amass quickly and wage an especially fierce battle against this type of donor tissue. Researchers are working to understand what it takes for a cross-species donor organ to protect itself. Gene therapy may hold great promise here, with the goal of transplanting the organ already equipped with the ability to defend itself.
Liver and Beta Cell Regeneration
The liver is both a factory (using nutrients and energy to fuel cell growth) and a filter (removing toxic substances from the bloodstream), with an astonishing ability to regenerate tissue. In fact, the liver is the only organ in the body with the ability to replace lost tissue with new growth, much like a starfish replaces an arm. So a small piece of liver transplanted into a child will, over time, grow to normal size. Researchers want to master this regeneration process, so they can accelerate it and ease the demand for donor organs, and tailor liver size for a closer donor/recipient match. Physician and clinical scientists are also studying beta cell regeneration, specialized cells that make insulin within the pancreas, which could offer new treatments for people with diabetes.
Another area of research study, vascular biology, examines blood flow to transplanted organs and tissues. Carbon monoxide gas and other novel protocols may help promote blood flow even as inflammation due to immune intolerance or rejection is underway. A steady and uninterrupted flow of oxygen-rich blood is essential to graft survival. Researchers look for ways to minimize the risk of blood clotting, stenosis (narrowing of the vessels), and other vascular damage in the transplanted organ. Researchers are also investigating improved methods for reestablishing the blood flow in organs that have been held in preservatives and packed for transport. Greater success in this area could help improve organ function and give doctors and patients more time to schedule the transplant surgery.
Researchers use bioinformatics, which incorporates chemistry, statistics, and computer science among other techniques, to address biological challenges from the molecular perspective. At BIDMC, researchers are studying the genome, the complete set of genes that make up our hereditary information and account for how we develop, look and behave. Armed with this information about donors and recipients, doctors can more accurately predict and anticipate organ rejection and hopefully tolerance. The information is also likely to be valuable to guide doctors in tempering the use of immunosuppressive drugs or in selecting the most effective drugs based on the genetic makeup of individual patients.
Quality of Life
Investigators in the Transplant Research Center are dedicated to discovery, to advancing the understanding of immune tolerance and other transplant-related challenges, and to moving gains from the laboratory into the patient care setting as quickly as possible. In all that we do, improving quality of life for patients and families is a universal goal.