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Allotransplantation - Tolerance Induction

Novel approaches at the TBRC for the treatment of end-stage organ failure, cancer and diabetes through allogeneic transplantation:

For an increasing number of patients suffering the ravages of illnesses such as kidney failure, coronary heart disease, and liver disease, transplantation of an organ provides the only hope for a prolonged life. Yet, with transplantation comes treatment-related complications, including the risk of organ rejection and the patient's dependence on life-long immunosuppressive drugs, which have side effects that weaken the patient's ability to fight infections and cancers. These problems can be avoided by the induction of “tolerance”, which is defined as the acceptance of a transplant without the need for immunosuppressive drugs. The induction of transplant tolerance is a major goal of the TBRC. Recently, a bone marrow transplant approach, which was first shown to be safe in cancer studies at the TBRC (see below) has been used to exploit the ability of bone marrow cells to re-educate the immune system for the induction of tolerance. This approach involves treating the recipient so that a mixture of bone marrow cells from both the recipient and the donor survive in the treated host. When this state of “mixed chimerism” is achieved, any organ or tissue from the same donor can be transplanted without the need for immunosuppression. The TBRC has pioneered the development of this approach, and has recently brought it to the first successful clinical trials of tolerance induction, now ongoing at Massachusetts General Hospital .

Bone marrow transplantation from healthy donors can cure leukemias and lymphomas. The major complication of this procedure, however, is a serious and sometimes lethal disease called “graft-versus-host disease” (GVHD), caused by immunologic reactions of the donor cells against the recipient. The increased severity of GVHD when mismatched transplants are attempted makes it necessary to find matched donors, which not all patients successfully find. Investigators at the TBRC have developed a less toxic way of performing mismatched and matched bone marrow transplantation in animal models that minimizes the complication of GVHD and which can nevertheless lead to powerful anti-leukemia/lymphoma effects. The procedure involves inducing mixed chimerism with relatively mild host treatments that deplete GVHD-inducing cells, then much later giving donor T cells, which attack the cancer. This pioneering approach has now been optimized and is providing successful new treatment of blood cell cancers in patients at the Massachusetts General Hospital .

Mixed chimerism is also potentially applicable to the treatment of type I diabetes. Bone marrow transplants have already been shown to prevent diabetes in experimental animal models of type I diabetes. However, the routine use of bone marrow transplantation for the treatment of autoimmune diabetes has been prohibited so far, largely because of the unacceptable toxicity associated with the host treatment needed to achieve marrow engraftment. Using the milder treatment regimen needed to induce mixed chimerism, TBRC investigators have shown that the procedure is able to reverse the autoimmunity that causes type I diabetes, thus preventing the development of disease in animal models. This approach is now being tested in preclinical, large animal models and will thereafter hopefully be applied to treatment of human type I diabetes.