Mixed Chimerism Approach to Induction of Transplant Tolerance: A Review of the Massachusetts General Hospital Experience

Abstract

URRENTLY, long-term immunosuppression is required for successful solid organ transplantation in humans. However, immunosuppressive regimens are associated with multiple complications, including infection, malignancies, and renal failure due to drug toxicity. In addition, although short-term allograft survival has increased significantly in the current era of immunosuppression, there has been little improvement in the rate of graft loss after the first posttransplantation year. Approximately 3% to 5% of all kidney transplants are lost in each subsequent year and chronic rejection accounts for almost half of the graft losses. 1 Many in the transplantation field believe that induction of donor-specific tolerance is the only way to control late alloimmune responses and to reduce the morbidity of immunosuppression. It has been shown that individuals with complete hematopoietic chimerism after myeloablative therapy and bone marrow transplantation will later be tolerant to solid organ transplants from the same donor. 2 However, the morbidity and mortality that result from the conditioning regimen is such that this method of tolerance induction is not appropriate for routine solid organ transplantation. Ildstad and Sachs 3 reported in 1984 that mice reconstituted with a mixture of donor and recipient strain bone marrow after ablative treatment developed mixed chimerism, where hematopoietic cells of both donor and recipient origin coexist in the recipient. These animals maintained their mixed chimerism and became tolerant to skin grafts from the donor strain. Later studies by Sharabi and Sachs 4 used nonmyeloablative protocols to achieve the same result. More recently, these studies were extended to large animal models. 5 Renal allograft tolerance through mixed chimerism has been reported in swine 6 and nonhuman primates. 7 In the monkey studies, combined hematopoietic stem cell and kidney transplants from the same donor resulted in mixed chimerism, but only for a few weeks. However, despite the loss of mixed chimerism, long-term tolerance of the kidney allograft was maintained. The low toxicity, lack of graft versus host disease (GvHD), and longterm tolerance that developed in these animals allowed similar protocols to be used in humans. The first trial of inducing renal allograft tolerance using mixed chimerism started in 1998 and involved HLA-matched bone marrow and kidney transplantation for multiple myeloma with renal failure secondary to the myeloma. 8,9 The protocol was easily justifiable for this patient population because patients with multiple myeloma are not candidates for conventional kidney transplants, and patients with end-stage renal disease (ESRD) are not candidates for conventional bone marrow transplantation (BMT). In addition, nonmyeloablative HLA-matched BMT was associated with a potent graft versus tumor effect, so this was the only treatment option available for these patients that could potentially treat their myeloma while restoring renal function. The conditioning regimen was derived from the nonhuman primate studies as well as experience with nonmyeloablative transplants for patients with hematologic malignancies. 10 Total body irradiation used in the animal studies was replaced with cyclophosphamide to provide more cytoreductive capability for the malignancy. Because the patients had renal failure, cyclophosphamide was limited to 2 doses at 60 mg/kg. Patients underwent thymic irradiation (7.0 Gy) on day 1 and antithymocyte globulin (ATG; 15 mg/kg) was given on days 1, 1, 3, and 5. Cyclosporine (CyA) was also started on day 1, with plans to discontinue it at 2 to 3 months posttransplantation. A kidney and bone marrow transplantation was performed from the same HLA- matched sibling donor on day 0. Donor leukocyte transfusions were given posttransplantation in an attempt to convert mixed chimerism to full donor chimerism to enhance the antitumor response without associated GvHD. Six such transplantations have been performed so far and