Sarah Goodwin

Kathi Ovnic
Holly Korschun
November 1, 1999

The National Institutes of Health (NIH) has selected Emory University’s kidney transplantation program as part of a new nationwide network that will conduct clinical trials using new research strategies to improve organ transplantation. Emory transplant surgeon Christian P. Larsen, M.D., D.Phil, will lead the nine kidney transplant research centers within the new Collaborative Network for Clinical Research on Immune Tolerance.

The clinical researchers hope to find ways to induce immune tolerance and selectively modulate the immune system by inhibiting harmful immune responses while keeping protective ones intact. The new therapy promises to improve the success of transplants as well as treatments for autoimmune diseases such as type 1 diabetes, lupus and arthritis.

More than 70 researchers and clinical specialists from 39 institutions in nine countries will work together in the new network. The seven-year initiative is funded by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), which contributed nearly $130 million to the effort; by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); and by the

Juvenile Diabetes Foundation International, which contributed $14 million.
"This collaboration brings together some of the brightest minds in immunology and flows from NIAID’s plan to accelerate clinical trials for novel approaches to modulate immune responses," said NIAID director Anthony Fauci.

"This is an extremely exciting opportunity for Emory and one that promises to fundamentally change the way we treat transplant patients," says Christian P. Larsen, M.D., D.Phil., Emory associate professor of surgery. Dr. Larsen and Thomas Pearson, M.D., D.Phil., are co-leaders of Emory’s program in kidney transplantation.

Drs. Larsen and Pearson and their Emory colleagues have gained international prominence for their groundbreaking research leading to new strategies to stop rejection of transplanted organs. In 1998 the NIH awarded physician-researchers in Emory’s Center for Transplantation a five-year, $7.5 million grant to help establish true immune tolerance in patients receiving organ transplants.

Organ transplant patients are required to take lifelong daily regimens of immunosuppressant medicines. Unfortunately these same medicines make them highly susceptible to viral and bacterial infections as well as cancer, kidney failure, diabetes, and osteoporosis. The medicines also are not effective past an average of eight years. About 30% of patients experience episodes of organ rejection, requiring hospitalization and extra doses of immunosuppresants.

"When we turn off immune responses to the transplant," explains Dr. Larsen, "we run into a potential problem of turning off the immune response to viruses or infectious agents. We need to be able to induce tolerance to the transplant while preserving protective immunity in the long-term to viruses.

Several years ago the Emory investigators developed the ability to simultaneously block two molecular pathways, CD40 and CD28, required by the immune system’s T-cells to reject invading microorganisms as well as transplanted tissues. Preventing the T-cells from getting these necessary "second-signals" is called a "costimulation blockade." This is one of the most exciting strategies to be tested by the Immune Tolerance Network.

Researchers from the U.S. Naval Medical Research Institute have used the double blocking therapy successfully in kidney transplants in rhesus monkeys. Drs. Larsen and Pearson have been studying ways to combine the costimulation blockade with a bone marrow transplant from the donor at the time of transplant. This strategy introduces a condition called chimerism, in which tissues or cells of one organism can co-exist with those of another. The researchers believe chimerism may make the costimulation blockade effective over the long term and eliminate the need for the immunosuppressant drug cyclosporine, which seems to interfere with the success of the costimulation blockade.

If the new clinical research network is able to demonstrate the safety and effectiveness of new strategies for immune tolerance it not only would free transplant recipients from the toxic side effects of daily immunosuppressant medicines, it also could lead to the "golden ring" of transplantation medicine – permanent, long-term acceptance of donor organs.


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