PITTSBURGH, May 26, 1998 — Getting a transplant recipient to accept an organ isn’t easy. A transplanted organ’s immune cells often fend off its new host, resulting in graft-versus-host disease. Moreover, a recipient’s body wages a vigorous immune response against the foreign-looking part, leading to transplant rejection. To date, successful transplantation has relied primarily on employing drugs to dampen these immune skirmishes. Now, researchers at the University of Pittsburgh are invoking another player in this drama -- the dendritic cell.
With recent awards for two grants totaling $2 million from the National Institutes of Health, Angus Thomson, Ph.D., D.Sc., is exploring the ways dendritic cells can enhance immune tolerance of new organs in transplant recipients. Dr. Thomson is a professor in the University of Pittsburgh’s department of surgery and department of molecular genetics and biochemistry, and he is the director of transplant immunology at the Thomas E. Starzl Transplantation Institute .
Dendritic cells are considered the master immune cells. As they circulate throughout the body, dendritic cells take molecules from foreign-looking materials (bacteria, viruses, and new organs) and present them to other groups of immune cells (lymphocytes) residing in specialized areas called lymph nodes. Depending on how presentations of these so-called antigens take place, dendritic cells either can stimulate their captive T cell audience to recognize the foreigner, multiply and go out to attack it, or instruct T cells to ignore the new occupant. The latter effect is what transplantation researchers want to understand and exploit.
"What we are doing in our current research studies is determining how dendritic cells play a natural role in enhancing transplant tolerance. With this information in hand, we are then set to design strategies for maximizing this process," noted Dr. Thomson.
One of Dr. Thomson’s projects focuses on inserting new genes into dendritic cells to promote transplant acceptance. Another initiative involves isolating and characterizing dendritic cells from the liver that appear critical in maintaining transplant tolerance in mice.
Dr. Thomson’s research team already has shown that when dendritic cells present antigens without certain co-stimulatory molecules, they don’t activate T cells, and the immune system’s attack on a transplanted tissue is blunted. In fact, the Pitt scientists found that these altered dendritic cells promoted the survival of cell and whole-organ transplants in mice that had not received drugs that are routinely administered to suppress immune rejection of an organ.
"One goal is to put genes for immunosuppressive cytokines into dendritic cells before re-introducing them into the body," added Dr. Thomson. Genes for certain cytokines (hormone-like substances) have been shown to markedly reduce the ability of dendritic cells to stimulate T cells.
According to Dr. Thomson, it may be possible to add genes for other factors to dendritic cells so that they precipitate programmed cell death among T cells they encounter. In this backdoor approach, the researchers could then harness dendritic cells to kill T cells that were previously primed to attack a transplant. An alternative approach is to insert genes into dendritic cells that encode molecules which promote the development of T lymphocytes capable of suppressing transplant rejection.
"We will assess the impact of these gene-modified dendritic cells on animal models of transplantation with the expectation of designing clinical trials with gene-engineered dendritic cells for patients receiving organ transplants," added Dr. Thomson.
In the other funded project, Dr. Thomson will determine how cytokines and matrix proteins alter dendritic cells in the liver and how these cells function after such changes. (Matrix proteins are found in the environment surrounding cells.) The research team will then study how these altered dendritic cells modify T cell populations in ways that promote transplant tolerance.
Dr. Thomson’s research team first discovered the importance of liver-derived dendritic cells in transplant tolerance in earlier work with mice. They showed that livers, but not other organs, could be transplanted between different mouse strains without subsequent organ rejection. The team then found and successfully cultured liver-derived progenitors of dendritic cells which lacked surface molecules needed to co-stimulate T cells with an antigen so they would reject a new organ.