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December 16, 1998 PATHOLOGY Donor Marrow Teaches Tolerance of Same-Donor TransplantsThe human thymus, hovering just in front of the heart, is also at the heart of research done by immunologist Megan Sykes, associate professor of surgery and of medicine at HMS and Massachusetts General Hospital. In the thymus, precursor cells differentiate into mature T cells, each uniquely able to recognize and respond to a different foreign antigen. More important to Sykes, who aims at using a new kind of bone marrow transplantation within and between species to induce immunological tolerance to transplanted tissue, thymus activity also ensures that the T cell population includes no traitors to the self.
By chance, some of the maturing immune cells grow receptors that recognize the body's own antigens. Let loose in the body, these T cells would attack and destroy a person's own cells. Instead, a fateful meeting in the thymus triggers a suicidal apoptosis of immature T cells: they die when they find their matched antigens in the major histocompatibility complex on the surface of large dendritic cells, a type of antigen-presenting cell. In this way, T cells intolerant to self antigens are deleted from the immune cell population. Sykes seeks to harness this mechanism to transplant organs without the need for lifelong immunosuppressive drugs to prevent rejection. Immature precursor cells that grow up to become dendritic and T cells originate in native bone marrow before moving to the thymus. Similarly, young dendritic cells from donor marrow also find their way to the host's thymus in transplant recipients. If a T cell recognizes a donor antigen on a donor dendritic cell, it responds as it would to recognizing a self antigen on a self dendritic cell--it kills itself so it will not mature and attack donor tissue. In this way, cells from donor marrow teach a host's immune system not to reject anorgan from the same donor. Sykes discovered that the role played by this tolerance mechanism worked in a new kind of bone marrow transplant, "mixed chimerism," eight years ago after coming to MGH. She heads the hospital's Bone Marrow Transplantation Section in the Transplantation Biology Research Center. Sykes received the 1998 American Society of Transplant Physicians Young Investigator Award for her contributions to transplantation immunology. She is one of the more than 30 investigators who have teamed up to cure type I diabetes by achieving successful transplants of insulin-producing islet cells. One of the hurdles to successful islet cell transplantation--and most other long-term transplantation--is inducing tolerance to the foreign antigens on the surface of transplanted islet cells without using long-term immunosuppressive drugs. Immunosuppressive therapy has made short-term transplants for older people successful, but at present young people with type I diabetes would face fewer problems on a lifetime of insulin injections than they would on chronic immunosuppressive therapy, whose side effects can include serious opportunistic infections and malignancies. In mice, bone marrow transplants from diabetes-resistant strains have already been shown to prevent insulitis, an inflammation of islet tissue before it is destroyed, as well as diabetes. Somehow, marrow transplants also seem to overcome another hurdle to islet cell transplantation--the autoimmunity problem that destroyed the host's original islet cells and would otherwise destroy transplanted islet cells. Unfortunately, bone marrow transplants cannot yet be used to treat type I diabetes because of the toxic host treatment needed to achieve marrow engraftment, and because of the complications associated with transplants. Toward Less Toxic Transplants Traditionally, doctors transplant bone marrow using the same toxic conditioning protocol developed to treat leukemia patients: total body radiation and chemotherapy to kill the host bone marrow cells and the T cells that would reject the donor marrow. Even for people who don't have cancers arising from the bone marrow, killing the host bone marrow is also believed to create the necessary physical space or regulatory feedback to allow new marrow to engraft. In mice, Sykes's colleague David H. Sachs the Paul S. Russell/Warner Lambert professor of surgery at HMS and MGH and director of the hospital's Transplantation Biology Research Center, had shown that he could achieve successful transplants with less toxic conditioning by using monoclonal antibodies aimed at depleting host T cells, combined with a lower dose of total body radiation and radiation of the thymus. Some host bone marrow survives the lower radiation, resulting in a state of "mixed chimerism" when the marrow engrafts. Looking for even less toxic transplant protocols, Sykes teamed up with Mohamed Sayegh, an associate professor of medicine at HMS and Brigham and Women's Hospital, who is the research director of the Laboratory of Immunogenetics and Transplantation at BWH. Sayegh is an expert in a second set of signals needed by the T cells to reject donor tissue. In a mechanism dubbed co-stimulation, a set of molecules on the antigen-presenting cells activates molecules on the T cell, in addition to the main antigen-receptor signal. One year ago on this project, Thomas Wekerle, a postdoctoral fellow in Sykes's lab, showed that two shots of antibodies to block the co-stimulatory response plus lower radiation were sufficient to permit bone marrow engraftment in mice. "The whole goal is tolerance," Sykes says, "so organs from
the same donor can be transplanted without In the mixed chimerism of the costimulatory blockade, the host mice accepted skin grafts, a notoriously difficult transplant, from the same mice that had donated the transplanted marrow, but rejected skin grafts of an unrelated group of mice. Sykes expects islet transplants can be achieved the same way--without toxic host treatment and without long-term immunosuppression. Successful outcomes in mice will be carried forward to larger animal models, primates and, finally, humans. Reducing Radiation Treatment In mice, Sykes is experimenting with ways to eliminate radiation altogether. Preliminary unpublished data suggest that increasing the amount of donor marrow by about 14 times, or providing about two thirds of the total bone marrow present in a healthy mouse, may overcome the need for radiation or even chemical suppression of the immune system. An ongoing clinical trial incorporating a modified transplant protocol for patients with aggressive, advanced leukemias and lymphomas has shown for the first time that mixed chimerism can be achieved, even with poorly matched marrow, in humans receiving relatively nontoxic conditioning treatments. The tumor responses have been mixed but highly encouraging. The clinical trial at MGH is headed by Thomas Spitzer, associate professor of medicine at HMS and MGH and head of the bone marrow transplant unit. Ultimately, researchers aiming to cure diabetes through transplants expect to use xenotransplantation, or transplants of islets from other species, such as pigs, to humans, if only because of the sheer quantity of islet cells needed to cure all the people with type I diabetes. Sykes's lab has demonstrated that the mixed chimerism approach can not only induce T cell tolerance to xenografts, but can also induce tolerance among B cells, another kind of immune cell that makes the antibodies that cause hyperacute rejection of xenotransplants. --Carol Cruzan Morton
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