Clues To Transplant Tolerance Linked To Infectious Disease Immunity Cell Traffic Key, Say Authors In New England Journal of Medicine

December 23, 1998

PITTSBURGH, Dec. 23 -- The process by which the human immune system takes little notice of certain infections is similar to the way it takes little notice of a transplanted organ under the most perfect immunological conditions, say two authors, one a Nobel laureate and the other the "father of transplantation," in this week's New England Journal of Medicine.

Thomas E. Starzl, M.D., Ph.D., professor of surgery and director, University of Pittsburgh Thomas E. Starzl Transplantation Institute; and Rolf M. Zinkernagel, M.D., professor of pathology and director, Institute for Experimental Immunology, University of Zurich, report that the mechanisms by which certain micro-organisms are able to exist in the human host closely resemble the mechanisms that confer permanent acceptance of a transplanted organ.

That antigens-foreign substances like those in micro-organisms and cells from a donor organ-migrate through the body to take up residence in various tissues is the common thread that explains how the body's immune system responds to both infectious diseases and organ transplants. The authors say this mechanism, involving a delicate balancing act, governs the immune system's response or nonresponse against infections, tumors, self, and transplanted organs from either human or animal donors.

"Although the relation between infection and transplantation immunity is complicated, the mechanisms and rules are basically the same," the authors write.

The review article is a convergence of theories from two separate medical specialties and draws upon the seminal works of Drs. Starzl and Zinkernagel.

In a 1992 Lancet article, Dr. Starzl observed that chimerism-the coexistence of donor and recipient immune cells-was a condition present in transplant recipients who had survived with their transplanted organs for up to 29 years. Donor leukocytes (white blood cells) and dendritic cells, which originate in bone marrow stem cells, were found in both lymphoid (spleen, lymph nodes, thymus) and nonlymphoid (skin, heart, liver) tissue of these recipients. In addition, recipient immune system cells were found in the transplanted donor organs. The discovery gave way to the belief that chimerism is a prerequisite for but not synonymous with long-term acceptance. It also confirmed that a transplant operation not only serves to replace organ function but it introduces as well a small piece of the donor's immune system into the recipient.

In this week's New England Journal of Medicine, Dr. Starzl, who performed the world's first liver transplant in 1963, and Dr. Zinkernagel, who shared the 1996 Nobel Prize in medicine for discoveries related to how the immune system recognizes virus-infected cells, elaborate on the process necessary for transplant tolerance. How the immune system defends itself against noncytopathic micro-organisms, which employs complex cell-mediated responses, provides the strongest parallels to transplant immunology.

Noncytopathic micro-organisms, including those that cause tuberculosis, hepatitis, herpes and warts, are less virulent than the cytopathic variety, like the bacteria for pneumonia, and they often can be accommodated by the host so that the two coexist. For instance, in some phases of the disease process of infection, noncytopathic antigens can be "noninjurious," as when a person carries hepatitis but has no symptoms. Such is the case with a stable organ transplant recipient whose immune system has accepted the graft.

Some noncytopathic micro-organisms-like warts-eventually draw little or no attention to themselves; they are essentially ignored by an immune system that is "indifferent" to presence in nonlymphoid tissues. Successful long-term organ acceptance could be achieved under the same immunological conditions.

"In time, a stable allograft [organ from a human donor] from this process may come to resemble a wart that never really induces an immune response nor is readily reached by immune effector mechanisms," the authors say.

Elaborating on both of their work, the two authors identify four closely linked steps required for completely successful organ engraftment. The process begins once the donor leukocytes home to recipient lymphoid tissues. Here, the donor cells induce the recipient anti-graft T cells in an immunological war game. Both types of cells-the T cells of the recipient that react against the donor and the donor T cells that react against the recipient-are left exhausted. No longer effective, they cancel each other out. These steps are called clonal exhaustion/deletion of the recipient response and clonal exhaustion/deletion of the donor-leukocyte response. The third step required is to maintain this neutral status of clonal exhaustion. Finally, in order to sustain acceptance of the transplanted organ, the donor organ must remain nearly depleted of its donor immune system cells, which are replaced with like-recipient cells. Not only are the donor leukocytes more useful at other sites within the recipient, but their excessive presence within the donor organ might raise a red flag that could signal a targeted host immune response.

In organ transplantation, Dr. Starzl's team has long believed, immunosuppressive drugs, at least initially, are necessary to oversee this process. The drugs control the two-way traffic of cells and are required to strike the delicate balance between the two divergent cell groups. Without the drugs, the patient's immune system may tilt in one direction, causing rejection and loss of the transplanted organ, or the other, causing graft vs. host disease, the complication that involves donor immune cells attacking the recipient's tissues.

With infectious diseases, the amount of exposure and the route of the antigen determine whether the host is able to clear the infection. Once a noncytopathic infection has taken hold, the immune system responds by releasing T cells that recognize the foreign invader. As with transplant organ acceptance, when clonal deletion and clonal exhaustion occur, the host is no longer able to recognize the infection effectively. In addition, the foreign invader may survive in the host by adapting itself, namely by hiding its antigenic profile. Many viruses do so by hiding inside host non-immune cells, from which they escape to lymphoid organs only under certain circumstances.

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