Director of Basic Research: Zhiguang Guo, M.D., Ph.D.
One of the major goals in the field of autoimmune disease and transplantation is to reprogram the host immune system to restore self-tolerance and to induce donor-specific tolerance with short-term immunotherapy. Although establishing hematopoietic chimerism is the most consistently successful approach to achieve tolerance, the toxicity of traditionally intensive irradiation as a conditioning therapy and the development of graft-versus-host disease (GVHD) after bone marrow transplantation (BMT) limited its clinical application. However, recent advances in hematopoietic stem cell transplantation indicate that the toxicity of conditioning therapy and the risks of GVHD can be reduced without compromising efficacy. Most important, only a certain level of donor chimerism, not full chimerism, is required to treat autoimmune disease and to induce transplant tolerance. Therefore, it is absolutely not necessary to use intensive conditioning therapy.
Islet transplantation has the potential to safely restore normoglycemia and insulin independence to patients early in the course of type 1 diabetes. Crucial to its wide clinical application is the development of a clinically applicable protocol to induce donor-specific tolerance to islet alloantigens and to restore self-tolerance to islet autoantigens in islet allograft recipients with autoimmune diabetes. Since type 1 diabetes is an autoimmune disease and is associated with defects in hematopoietic stem cells, combining hematopoietic stem cell and islet transplantation may be an ideal therapeutic approach.
Chemically induced diabetic mouse models have generally been used for islet transplantation and immune tolerance can be variously induced in these models. But they cannot truly reflect the clinical setting of autoimmune diabetes. For this reason, the NOD mouse has been extensively used as an animal model of human type 1 diabetes. The development of diabetes in NOD mice has been attributed to autoreactive T cells that infiltrate pancreatic islets and specifically destroy insulin producing islet beta cells. Islet allografts in diabetic NOD mice are destroyed by both alloimmune and recurrent T-cell mediated autoimmune responses. Thus, the NOD mouse model is the best available for experimental islet transplant research and for the investigation of clinically relevant methods to induce and restore tolerance.
A multitude of strategies prevent development of diabetes in the NOD mice. Yet, it has proven extremely difficult to prevent rejection and autoimmune destruction and to restore tolerance in overtly diabetic NOD mouse recipients. The effective approach is to establish mixed allogeneic chimerism, thereby simultaneously inducing donor-specific tolerance to islet allografts and restoring self-tolerance to islet autoantigens by using sublethal irradiation as a conditioning therapy. Since NOD mice are irradiation-resistant, high doses of irradiation must be given to establish mixed chimerism compared with other mouse strains. But irradiation, particularly at high dose, is not clinically favorable.
To develop a less toxic, more clinically applicable approach to achieve mixed chimerism in islet allotransplant recipients with autoimmune diabetes, we have investigated several new protocols for inducing donor chimerism in mice. Recently, we successfully induced donor chimerism in mice using a nonmyeloablative and irradiation-free approach. Our studies showed that posttransplant donor lymphocyte infusion (DLI) increases donor chimerism and induces donor-specific tolerance to islet allografts in diabetic NOD mice after establishing a low level of donor chimerism by simultaneous hematopoietic stem cell and islet transplantation under a relatively nontoxic protocol that is nonmyeloablative and irradiation-free.
Although two or more donors are required for a successful human islet allotransplantation under the current Edmonton protocol, human islet autotransplant recipients after pancreatectomy need fewer islets per recipient than the islet allotransplant recipients. We determined whether the islet mass required to reverse diabetes could be significantly reduced in spontaneously diabetic NOD mice after establishing a substantial level of donor lymphocyte chimerism, as compared with the islet mass required for successful allogeneic islet transplantation in immunosuppressed diabetic NOD mice. Our results demonstrate that a high number of islets are required to reverse diabetes in diabetic NOD mice under immunosuppression comparable to the Edmonton protocol. However, a low islet number is sufficient to restore normoglycemia in diabetic NOD mice with a substantial level of donor chimerism. These data suggest that a small number of transplanted islets are sufficient to reverse diabetes in those diabetic NOD mice whose alloimmune response and autoimmune response were abrogated by pretransplant induction donor-specific tolerance.
Currently, we are investigating the fundamental concepts and the mechanism related to inducing donor-specific tolerance to islet allografts in diabetic NOD mice by posttransplant DLI and to explore a novel approach to induce donor specific tolerance by using posttransplant donor regulatory T cell infusion.
Our research projects are highly relevant to inducing transplant tolerance to alloantigens and restoring self-tolerance to autoantigens, and may have important impacts on developing novel approaches for inducing transplant tolerance and treating autoimmune diseases.
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