Aug. 26, 1999 While organ transplants have been one of the great success stories of 20th century medicine, one of the downsides of the lifesaving procedures has been the requirement that organ recipients take powerful drugs to suppress their immune system for the rest of their lives. Now for the first time, physicians at the Massachusetts General Hospital (MGH) have deliberately induced a state of immune tolerance in a transplant recipient, enabling the patient to discontinue drug treatment without rejecting a transplanted kidney.
The patient, a woman who developed kidney failure as a result of a cancer of the bone marrow called multiple myleoma, received both a kidney transplant and bone marrow transplant from her sister in September 1998. As reported in the August 27 issue of Transplantation, the physicians' goal was to induce a state of mixed chimerism, in which the immune systems of donor and recipient are blended in a way that prevents rejection of the transplanted kidney by the recipient's body and suppresses an attack of the donor's immune cells on the recipient's organs, a dangerous condition called graft-versus-host disease. While the strategy was used in this patient to treat both kidney failure and the underlying malignancy, the accomplishment is an important milestone for the thousands of patients who require organ transplants each year.
"This is a first step toward the day when transplant recipients can be made tolerant to their donors' organs without the risks and costs of life-long immunosuppressive drugs," says Benedict Cosimi, MD, chief of the MGH Transplantation Unit and a primary author of the Transplantation paper. "We hope to be able to use this approach with less-closely-matched donors, providing even more options for patients needing transplanted organs."
Multiple myeloma is a cancer of the bone marrow that causes the proliferation of abnormal plasma cells. The result can be reduced levels of red cells and platelets, tumors at multiple sites around the body (hence multiple myeloma), kidney or heart failure, or life-threatening infections. The disease has no cure, and treatments designed to help patients live longer have varying levels of success. Bone marrow transplantation is tried for some patients, but many recipients experience graft-versus-host disease and others are unable to withstand the usual preparation for the procedure, which involves complete destruction of the bone marrow by chemotherapy or radiation.
The procedure described in the current report uses a new, less toxic preparation for bone marrow transplant that was developed at the MGH Transplantation Biology Research Center (TBRC). As described in the May 22 issue of The Lancet, patients are prepared for the transplant with a combination of mild chemotherapy and antibodies against T cells, the immune cells that attack transplanted tissues. This approach allows the patient to accept the donor marrow but preserves most of his or her own marrow, leading to the blended immune system that characterizes mixed chimerism. (The name comes from the chimera, a creature in ancient Greek mythology that was made up of parts from various animals.) While the chimeric state keeps donor cells from attacking the recipient's healthy tissues, tumor cells are not protected. Additional post-transplant infusions of donor white blood cells can further enhance the anti-tumor effect in chimeric recipients.
The TBRC, in collaboration with BioTransplant Incorporated of Charlestown, Mass., has been studying mixed chimerism and its possible applications for both inducing tolerance of organ transplants and fighting blood-cell cancers for several years. The patient described in the Transplantation article was unusual in needing both applications and having no other viable option. Her myeloma caused her kidneys to fail, and she did very poorly on dialysis. Her cancer made her ineligible for a regular kidney transplant, and her kidney failure made her unable to tolerate the toxicity of standard bone marrow transplant preparation.
After the double transplant from her sister, the patient had normal kidney function with no sign of graft-versus-host disease. While she received cyclosporine right after the transplant, the immunosuppressant was tapered off and discontinued on the 73rd day after the procedures. Two post-transplant donor-white-blood-cell infusions were also given in an attempt to suppress her myeloma, which remains at a nearly undetectable level at this time.
Thomas Spitzer, MD, director of the MGH Bone Marrow Transplant Program and lead author of the Transplantation paper, says, "The great results we've seen in this patient - who probably would not have survived without these transplants - raises the possibility that other patients with blood-cell cancers and kidney failure may be successfully treated with the same approach."
The researchers are particularly intrigued by the fact that, while the effect of mixed chimerism - no conflict between the donor and recipient immune systems - continues in this patient, the actual chimeric state seems to be disappearing. In fact, donor cells can no longer be found in the recipient's marrow. "This kind of transient chimerism had been observed in the preclinical studies we have performed in monkeys, and we need to understand better the mechanism behind this phenomenon," says David Sachs, MD, director of the TBRC and a study coauthor. "One theory is that the donor kidney itself helps the recipients' body maintain a state of tolerance."
The animal studies that first achieved mixed chimerism were conducted in Sachs's TBRC laboratory, and the concept of applying the chimeric effect to blood-cell cancers was developed by TBRC researcher Megan Sykes, MD, another study coauthor. The procedures and their application to both transplant tolerance and cancer treatment have been licensed to BioTransplant Incorporated (Nasdaq:BTRN).
This study was supported by grants from the National Heart, Lung and Blood Institute; the National Institute for Allergy and Infectious Disease; and BioTransplant Incorporated.
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