Specifically, the researchers will try to harness a subset of dendritic cells that have unique tolerance-enhancing qualities to see whether the cells can be directed to influence the acceptance of transplanted donor kidneys, including kidneys that are immunologically mismatched to the recipient. The studies, which will focus on nonhuman primates, are based on other animal research and evidence in transplant patients successfully weaned off all immunosuppression that show a subpopulation of dendritic cells might play a key role in convincing the immune system to accept a transplanted organ.
"We are hopeful that a clinical strategy to induce tolerance in transplant patients will emerge from these studies in nonhuman primates. Indeed, it is everyone's goal working in the field of transplantation to identify ways to promote the permanent, drug-free acceptance of transplanted organs," said the study's principal investigator, Angus W. Thomson, Ph.D., D.Sc., professor of surgery and immunology at the Thomas E. Starzl Transplantation Institute and the University of Pittsburgh School of Medicine.
The grant builds on several findings that have been reported in recent years by Dr. Thomson and members of his research team. In one set of studies, a pre-transplant infusion of these dendritic cell subtypes, which derive from lymphoid tissue or blood, allowed for prolonged survival in a mouse heart transplant model, even without the use of drugs to control rejection. In contrast, the better-known myeloid dendritic cells accelerated the rejection response.
According to the researchers, transplant patients who are off immunosuppression have fewer of these type of dendritic cells normally associated with rejection than transplant patients who are prone to rejection or who rely on anti-rejection drugs to maintain their transplanted organ. They also appear to have more of the "good" dendritic cells, according to the Pitt researchers.
Dendritic cells, a rare type of white blood cell that is present in all tissues, are known for their ability to identify and present antigens, or foreign substances, to other immune system cells that are programmed to destroy the antigen. Until recently, they have been thought only to be involved in prompting the rejection process. But the subtype of dendritic cells apparently has the opposite effect by regulating the immune response and determining that a frontline attack against the organ by T cells is unwarranted. T cells are the soldiers for the immune system that take their cue from other key cells.
Working with Dr. Thomson on the five-year grant are the following co-investigators from the University of Pittsburgh: Patrick T. Coates, M.D., Ph.D.; Simon M. Barratt-Boyes, D.V.M., Ph.D.; Adrian E. Morelli, M.D., Ph.D.; Albert D. Donnenberg, Ph.D.; Michael A. Murphy-Corb, Ph.D.; and Anita M. Trichel, D.V.M.
Christian P. Larsen, M.D., D. Phil, and Thomas C. Pearson, M.D., D.Phil, from Emory University and Yerkes Primate Research Center in Atlanta, are co-investigators as well.
CONTACT:
Lisa Rossi
Michele Baum
PHONE: (412) 647-3555
FAX: (412) 624-3184
E-MAIL:
RossiL@upmc.edu
BaumMD@upmc.edu