Yale group launches new effort to understand why organ transplants fail

By 11 a.m., Yinong Wang, M.D., is performing his fifth transplant procedure of the day. Each one is the same, and not what you would expect: Prepare a snippet of blood vessel from a donor patient and slip it into the aorta of the anesthetized recipient. Suture and close. Repeat.

Though Wang is indeed a surgeon, it would be misleading to call these recipients patients. They are mice. The delicate suturing is part of a long-term study to determine why coronary arteries narrow over time and become blocked. By using so-called severe combined immunodeficiency (SCID) mice that have been bred without the genes necessary to create T and B cells, the study’s designers are able to introduce immune cells from one human and see how they interact with the blood vessels of another. A week after the microsurgery, the study team will introduce T cells and macrophages from the second human into the mouse’s circulation, then watch for signs of inflammation in the transplanted artery. It’s a model that mimics the real-life battle that occurs after the transplantation of a heart, kidney or liver and which can speed the rejection of the organ. Wang, along with George Tellides, M.D., HS ’93, Marc I. Lorber, M.D., and Jordan S. Pober, M.D. ’77, Ph.D. ’76, HS ’78, is interested in seeing how the cytokine interferon gamma may affect that interaction.

The SCID-mouse model for inflammation is one way Yale scientists are exploring common ground between the basic science of the vessel walls and the clinical problems of organ transplantation. Their efforts were formalized at the medical school in 2000 with the establishment of the Interdepartmental Program in Vascular Biology and Transplantation (VBT), a working group of 24 scientists and physicians in 10 departments.

“Our goal is not to become the world’s largest transplant program but to change the ways that transplantation is being done,” said Pober, the program’s director.

VBT has succeeded in attracting new support from the NIH in the form of a $6.4 million program project grant, and is embarking on a collaboration with Cambridge University funded by Britain’s Medical Research Council. The Interdisciplinary Program in Clinical Transplantation (IPCT), the VBT’s companion program, also received $2.5 million last year in the first round of funding from the Yale-New Haven Medical Center’s new Clinical Program Development Fund. More than a dozen visiting scientists have presented their work in the program’s seminar series.

The science in this area is promising, and that’s a good thing. With long waiting lists for organ transplants (4,323 people died last year waiting for a heart, lung, kidney, liver, intestine or pancreas) and a shortage of donors, transplant physicians are eager to find new ways of protecting those scarce organs that are available.

The new generation of immunosuppressive drugs that emerged during the past decade has greatly reduced the threat of acute rejection immediately following a transplant. Solving the problems of chronic rejection, which leads to the failure of transplanted organs within the first year, is the next step in the effort to reduce demand and stretch supply. Creating a new source of organs through the creation of engineered pig organs, or xenografts, is another. Yale scientists are working in both areas, as well as searching for ways to create artificial tissues or synthetic skin to improve graft viability.

Applying the rapidly unfolding science of immunology to clinical problems will make a huge difference, said Lorber, director of the IPCT. “Most organs that fail do so not because of the failure of immunosuppression in the early post-transplant period. Rather they fail over a period of months to years from the process of chronic rejection,” said Lorber. “We believe that understanding this process may dramatically improve the long-term outlook.” Toward that end, the group’s research is focused on the possibility that chronic rejection may result from an attack by the immune system on the blood vessels, Lorber added. The same process that causes coronary artery disease and heart attacks may be similar to the events leading to chronic organ rejection.

Hence, the group’s interest in SCID mice and the “vascular remodeling” they’ve observed in the studies of transplanted vessels. After doing more than 100 of the procedures, they reported last May in Nature that interferon gamma actually contributed to a thickening of the vessel wall and sped the division of smooth muscle cells, contrary to the conventional wisdom. Both factors contribute to the narrowing of the arteries that supply blood to transplanted organs.

For Tellides, chief of cardiac surgery at the Veterans Administration hospital in West Haven, the finding is an important step. “By knowing which molecules exacerbate vascular disease, we can improve diagnosis and eventually treatment,” he said. “Right now we can only bypass the blockages.”