Chimerism—the coexistence of donor and recipient cells—is a major theme of scientific investigation at the University of Pittsburgh Medical Center’s (UPMC) Thomas E. Starzl Transplantation Institute. Under the direction of Thomas E. Starzl, M.D., Ph.D., research in this area has offered significant contributions to the understanding of transplant immunology. Having laid this groundwork, researchers are continuing to work toward more scientific and clinical advancement.
UPMC researchers view chimerism as a prerequisite for but not synonymous with long-term organ acceptance. To better understand chimerism and transplant tolerance, a number of basic science and clinical studies are underway taking aim at the nuances and complexities of the immune system.
Recipients of livers and kidneys, who had survived with their transplanted organs for up to 29 years, provided the first clues to Dr. Starzl and his team that chimerism was a naturally occurring phenomenon after whole organ transplantation. Studying these patients also gave way to the belief that chimerism plays a major role in organ acceptance as the first stage in the development of whole organ tolerance. In humans, organ acceptance can be defined as persistence of organ function with anti-rejection or immunosuppressive drugs. However, if the organ sustains its function with very low or no immunosuppression, researchers conclude that a functional donor-specific tolerance has been induced.
In 1992, biopsies taken from the long-surviving patients’ transplanted organs, lymph nodes, skin and other tissues revealed that donor leukocytes, or white blood cells, had migrated from the transplanted organs to recipient tissues, where they persisted years after transplantation. Researchers also found recipient cells continuing to coexist with donor cells within the transplanted organs. Such an observation provided confirmation that in organ transplantation, surgeons are not only replacing organ function but they are also exposing the recipient to the donor’s immune system.
Among the types of donor cells that most often migrate to other tissues are stem cells, from which all cells derive, and dendritic cells, which originate in bone marrow. Dendritic cells capture antigens (foreign or self particles) and present them to T and B cells, cells important in modulating immune responses to infections, cancer and transplanted organs. Researchers hypothesize that in order for chimeric dendritic cells to induce donor-specific tolerance, they must either present a foreign antigen in an altered way, thus allowing for its acceptance, or they must directly inhibit T cells that are reacting against the foreign antigen. Today, research continues to understand more fully the role of this cell in transplant acceptance and functional tolerance.
Current understanding suggests that four closely linked steps are required for completely successful organ engraftment. The process begins once the donor leukocytes home to recipient lymphoid tissues. Here, the donor cells induce the recipient anti-graft T cells in an immunological war game. But both types of cells—the T cells and the donor leukocytes—are left exhausted and ineffective in the process and essentially cancel each other out. These first two steps accomplished—clonal deletion of the recipient response and clonal deletion of the donor-leukocyte response—the third step required is to maintain this neutral status, called clonal exhaustion. Finally, in order to sustain acceptance of the transplanted organ, the donor organ must remain nearly depleted of its donor immune system cells and replaced with like-recipient cells. Not only are the donor cells more useful at other sites within the recipient, but their presence within the organ might raise a red flag, thus signaling a targeted host immune response.
Immunosuppressive drugs are required, at least initially, to allow the donor cells to migrate and coexist peacefully with recipient cells, Dr. Starzl and his team believe. Perhaps at first acting as traffic directors, the drugs permit the immune cells to travel within the body until arriving at their permanent destinations. Ultimately, the drugs may work by striking a delicate balance between the two divergent cell groups. Without the drugs, the patient’s immune system may tilt in one direction, causing rejection and loss of the transplanted organ, or the other, causing graft vs. host disease (GVHD), the complication that involves donor immune cells attacking the recipient’s tissues.
While drugs may be needed to strike the delicate balance of donor and recipient cells thereby establishing the stable chimeric environment necessary for acceptance, new evidence suggests the drugs may not be needed in the long run to maintain this balance in a significant number of patients, contrary to traditional belief.
At the UPMC, several long-term liver transplant patients, who had received their transplants between five and 21 years ago, have been successfully weaned from immunosuppressive drugs as part of a controlled protocol. Others, including children, with severe complications of immunosuppression, have also been successfully weaned. Customarily, it has been thought that transplant recipients need to take drugs for the rest of their lives to prevent the natural defenses of their immune systems from attacking the transplanted organs. Normally with suppressed immune systems, these patients are constantly susceptible to infections, some of which can be deadly. However, if carefully managed by a physician, some transplant recipients can either completely stop or drastically reduce their doses of drugs without incidence of rejection, the ongoing UPMC study has found. For transplant recipients, a life without immunosuppression means a life free of unpleasant side effects, associated medical complications as well as the risk for infections. Chimerism research may ultimately improve the quality of life for all transplant recipients, especially children, whose outward appearance and growth can be negatively affected by the drugs they take.
Encouraged by these results, the UPMC researchers are investigating ways to augment chimerism. One method under clinical study at the UPMC involves providing an added supply of donor immune system cells at the time of transplantation. Solid organ transplantation and simultaneous bone marrow infusion from the same donor have been found to be safe, with little risk of GVHD, and to augment the level of chimerism. Long-term follow-up of patients will determine if it promotes the acceptance of the transplanted organs.
Since Dec. 1992, more than 225 patients have received bone marrow infusions at the time of their liver, kidney, pancreas, lung or heart transplants. In addition, some patients have also received pancreatic islet cells with either kidney or liver transplants. Unlike similar studies elsewhere, the UPMC team does not pretreat patients with radiation, nor does the team modify the bone marrow in any way.
With some patients beyond the five-year milestone, researchers will begin to assess whether these patients can be partially or completely weaned of the need for immunosuppressive drugs.
Neither chimerism research nor its significance is limited to human-to-human transplantation. Much of the basic research is conducted in cross-species animal models, and efforts to study chimerism in humans undergoing xenotransplantation (cross-species transplantation) have also been made at the UPMC. In the world’s first baboon-to-human liver transplant recipient, baboon cells were found in the patient’s blood stream during his life, and at autopsy, cells were found in his heart, lungs, kidneys and lymph nodes. The second baboon liver recipient, who received an infusion of bone marrow cells from the baboon donor at the time of his liver transplant, also had evidence of chimerism. However, his death only 26 days after transplantation made it difficult to assess the benefits of the bone marrow infusion. Research continues to be conducted to fully evaluate the significance of chimerism in the acceptance of xenotransplanted organs.