EMORY INVESTIGATORS DEVELOP IMPROVED TOLERANCE STRATEGIES FOR ORGAN TRANSPLANTATION

November 1997

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Two Emory University investigators studying the mechanisms of immunosuppression in organ transplantation are growing closer to achieving true "immune tolerance" † the ability of patients to accept donor organs and tolerate them over the long term without the need to depend on immunosuppresive medicines.

The Nov. 22 issue of the British medical journal The Lancet describes recent developments in the strategy developed last year (Nature, 1996) by Christian P. Larsen, M.D., D.Phil., and Thomas C. Pearson, M.D., D.Phil., Emory associate professors of surgery. The two investigators were able to stop rejection of transplanted organs in laboratory mice by simultaneously blocking two important pathways that stimulate the action of T-cells, one of the immune system's primary weapons in fighting off invading microorganisms and transplanted tissues.

Larsen and Pearson used reagents that blocked the molecule pairs CD28-B7 and CD40-gp39, which are present on the surface of cells and important in the function of the immune system. The CD28-B7 pair provides a "second signal" necessary for T-cell activation, while the CD40-gp39 pair is important for B-cell, macrophage, endothelial cell and T-cell activation, all of which are involved in immune defense. Larsen and Pearson found that if they treated mice to block these two signalling pathways at the time of transplant they could maintain grafts of transplanted tissue for long periods of time without using any other immunosuppressive medicines.

Recently, researchers from the U.S. Naval Medical Research Institute in Bethesda, MD, used the double blocking therapy successfully in kidney transplants in rhesus monkeys, who were still healthy six months after transplant despite being given no immunosuppressive medications (Proceedings of the National Academy of Science, August 5, 1997).

In the October 1997 issue of Current Opinion in Immunology, Larsen and Pearson further describe the crucial role played by CD40 and how knowledge about the influence of this molecule promises to yield new therapeutic agents that might ultimately produce human transplant tolerance. The CD40 pathway may help answer one of the most difficult questions of transplantation, says Dr. Pearson: "Why can the immune response be suppressed or blocked for a long while yet resurface much later to reject transplanted organs? In our studies of mice," he says, "we found that even though engrafted tissues were tolerated for much longer periods with the double blocking strategy, eventually the grafts were rejected."

In recent experiments combining other therapies with the blocking mechanisms, however, Larsen and Pearson believe they may be close to achieving true tolerance - "the golden ring that the transplant community has been seeking all along," says Dr. Pearson.

"Immunosuppression medicines, which patients must take as long as they live, work well in the short-term, where survival rates are really good for heart, liver, and kidney transplants," he notes, "but the grafts continue to be lost in the long term. The other side of the coin is that the immunosuppression medicines are non-specific, so not only do they block the immune response to the transplant, but also to viral and bacterial infections and they may lead to complications such as diabetes, osteoporosis, kidney failure and malignancies."

The Emory researchers are hopeful that recently completed experiments using the blocking strategy in a xeno-transplant model (organ or tissue transplants between animals of different species) will eventually help make xeno-transplants available in humans, greatly increasing the number of available organs. Currently, organs for transplant are in short supply, and almost 4,000 Americans a year die while waiting for a compatible donor.

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