Promotion of Pancreatic Islet Allograft Survival By Intrathymic Transplantation of Bone Marrow

Abstract

An important goal in the treatment of insulin-dependent diabetes by pancreatic islet transplantation is the development of strategies that allow permanent survival of islet allografts without continuous host immunosuppression. In this study, we demonstrate that inoculation of allogeneic bone marrow into the thymus of adult rats treated with a single dose of anti-lymphocyte serum induces an unresponsive state that permits survival of subsequent pancreatic islet allografts transplanted to an extrathymic site. This effect is donor specific, cannot be reproduced by systemic administration of bone marrow, and is associated with persistence of chimeric cells in the thymus of the recipient. In addition, lymph node cells from long-term recipients of intrathymic bone marrow display markedly reduced proliferative responses to donor alloantigens in mixed lymphocyte culture. Interaction of maturing thymocytes with foreign alloantigens may produce the unresponsiveness. This model offers a potential approach for establishing donor-specific allograft acceptance in adult recipients. Diabetes 41:771-75, 1992 I nduction of donor-specific unresponsiveness represents the ideal approach for securing permanent survival of pancreatic islet allografts because it precludes rejection without the need for chronic immunosuppression of the host. Although it was demonstrated >30 yr ago that immunologic tolerance can be readily achieved in rodents by inoculation of donor-strain lymphohematopoietic cells at birth, tolerance induction in adult recipients has been more difficult, requiring extenFrom the Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.Address correspondence and reprint requests to Dr. Ali Naji, Hospital of the University of Pennsylvania, Department of Surgery, 3400 Spruce Street, Philadelphia, PA 19104.Received for publication 1 January 1992 and accepted 23 January 1992.sive preparative conditioning by irradiation and/or treatment with nonspecific cytoablative chemotherapy (1-4). We previously reported that pancreatic islets implanted in the thymus of allogeneic adult rats survived permanently and, in addition, rendered the recipients tolerant of donor alloantigens (5). In this study, the efficacy of this approach in promoting transplantation tolerance was assessed by examining the impact of intrathymic inoculation of allogeneic bone marrow cells (BMC) on the survival of extrathymic transplants of pancreatic islets. We demonstrate that rats pretreated with an intrathymic injection of allogeneic BMC are rendered specifically unresponsive to donor alloantigens and permanently accept subsequent donor-strain islet allografts. Furthermore, this result can be accomplished without need for other methods known to prolong islet allograft survival, such as pretransplant modulation of allograft immunogenicity or chronic immunosuppression of the recipient (6). RESEARCH DESIGN AND METHODSBone marrow inoculation and islet transplantation.

Induction of Donor-Specific Tolerance to Rat Islet Allografts by Intrathymic Inoculation of Solubilized Spleen Cell Membrane Antigens

“…different methods: treating recipients with irradiation (7) or cyclophosphamide (8); and by intrathymic injections of pancreatic islets, bone marrow, splenic, hepatic or glomerular cells (9)(10)(11)(12)(13). Our present studies confirm that intrathymic inoculation of allogeneic islets can induce donor-specific tolerance.…”

Genetically Engineered Pancreatic β‐Cell Lines for Cell Therapy of Diabetes

“…4 Thus, the optimal treatment of IDDM is likely to be the replacement of the damaged β cells with intact β cells. Protection of the transplanted cells from immune rejection by the host.In addition to graft rejection, the IDDM host is primed to destroy β cells, therefore recurring autoimmunity is a major concern. The experimental approaches developed in recent years to prevent transplant rejection, such as encapsulation, induction of donor‐specific tolerance, 5,6 and various genetic manipulations of the donor cells to resist immune attacks, 7,8 may not be sufficient in an autoimmune environment. IDDM usually develops in young children, therefore any alternative therapy would need to offer a life‐long solution.…”

“…In addition to graft rejection, the IDDM host is primed to destroy β cells, therefore recurring autoimmunity is a major concern. The experimental approaches developed in recent years to prevent transplant rejection, such as encapsulation, induction of donor‐specific tolerance, 5,6 and various genetic manipulations of the donor cells to resist immune attacks, 7,8 may not be sufficient in an autoimmune environment.…”

Obesity and Diabetes

“…Cell encapsulation in polymer membranes has reached the stage of clinical trials, in patients with neural disorders. Intra-thymic transplantation of islets and BM has shown promise in induction of donor-specific tolerance (Posselt et al 1990(Posselt et al , 1992. In addition, a variety of immune effector molecules have been employed in attempts to manipulate donor cells genetically to resist immune attacks (Lau et al 1996;Pearson et al 1996).…”