This conditioning regimen prevented hyperacute rejection but was ineffective in preventing the return of Ab, which was associated with the development of acute humoral rejection with features of coagulopathy. No baboon developed anti-pig Ab other than alphaGal Ab. Further modifications of the protocol directed toward suppression of production of Ab are required to successfully induce tolerance to pig organs in baboons.

Bone marrow transplantation (BMT) has considerable potential for the treatment of malignancies, hemoglobinopathies, and autoimmune diseases, as well as the induction of transplantation allograft tolerance. Toxicities associated with standard preparative regimens for bone marrow transplantation, however, make this approach unacceptable for all but the most severe of these clinical situations. Here, we demonstrate that stable mixed hematopoietic cell chimerism and donor-specific tolerance can be established in miniature swine, using a relatively mild, non-myeloablative preparative regimen. We conditioned recipient swine with whole-body and thymic irradiation, and we depleted their T-cells by CD3 immunotoxin-treatment. Infusion of either bone marrow cells or cytokine-mobilized peripheral blood stem cells from leukocyte antigen-matched animals resulted in stable mixed chimerism, as detected by flow cytometry in the peripheral blood, thymus, and bone marrow, without any clinical evidence of graft-versus-host disease (GvHD). Long-term acceptance of donor skin and consistent rejection of third-party skin indicated that the recipients had developed donor-specific tolerance.

Mixed hematopoietic chimerism may provide a treatment for patients with nonmalignant hematologic diseases, and may tolerize patients to organ allografts without requiring chronic immunosuppression. However, the toxicity of the usual conditioning regimens has limited the clinical applicability of this approach. These regimens generally include some level of whole body irradiation (WBI), which is thought to facilitate engraftment either by making room for donor hematopoietic stem cells or by providing sufficient host immunosuppression to enable donor cells to engraft. Here, we have established mixed chimerism across both minor and major histocompatibility barriers in swine, by using high doses of peripheral blood stem cells in the absence of WBI. After mixed chimerism was established, swine leukocyte antigen-matched (SLA-matched) donor skin grafts were tolerated and maintained for a prolonged period, whereas third-party SLA-matched skin was rejected promptly. Donor-matched kidney allografts were also accepted without additional immunosuppression. Because of its low toxicity, this approach has potential for a wide range of clinical applications. Our data may indicate that niches for engrafting stem cells are filled by mass action and that WBI, which serves to empty some of these niches, can be omitted if the donor inoculum is sufficiently large and if adequate host T-cell depletion is achieved before transplant.

In living donor liver transplantation, the safety of the donor operation is the highest priority. The introduction of the right lobe graft was late because of concerns about donor safety. We investigated donor liver regeneration by the types of resected segments as well as recipients to assess that appropriate regeneration was occurring. Eighty-seven donors were classified into 3 groups: left lateral section donors, left lobe donors, and right lobe donors. Forty-seven adult recipients were classified as either left or right lobe grafted recipients. Volumetry was retrospectively performed at 1 week, 1, 2, 3, and 6 months, and 1 year after the operation. In the right lobe donor group, the remnant liver volume was 45.4%, and it rapidly increased to 68.9% at 1 month and 89.8% at 6 months. At 6 months, the regeneration ratios were almost the same in all donor groups. The recipient liver volume increased rapidly until 2 months, exceeding the standard liver volume, and then gradually decreased to 90% of the standard liver volume. Livers of the right lobe donor group regenerated fastest in the donor groups, and the recipient liver regenerated faster than the donor liver. Analyzing liver regeneration many times with a large number of donors enabled us to understand the normal liver regeneration pattern. Although the donor livers did not reach their initial volume, the donors showed normal liver function at 1 year. The donors have returned to their normal daily activities. Donor hepatectomy, even right hepatectomy, can be safely performed with accurate preoperative volumetry and careful decision-making concerning graft-type selection. Liver Transpl 14: [1718][1719][1720][1721][1722][1723][1724] 2008 Living donor liver transplantation (LDLT) plays an important role because of cultural attitudes and the scarcity of cadaveric donations in Japan.1 LDLT involves an ethical problem: because the donor operation is performed on a healthy person, donor safety is the highest priority and requires special attention. LDLT was a treatment first for infants, then for children, and finally for adults. Although a left lobe graft provides enough volume for pediatric recipients, some adult recipients require a right lobe graft. There is little question about donor safety, on the basis of remnant liver volume requirements alone, if only a left lateral section and left lobe graft are procured. It is in the use of a right lobe that issues of donor safety come into play. Several authors have studied donor safety, especially with respect to surgical complications and clinical courses.2,3 Donor safety from various standpoints should be studied further in order to gain insight into the postoperative recovery pattern of a healthy person and to prevent complications.Although the human liver can tolerate more than 70% hepatectomy, 4 unfortunately some living donors have died of excessive loss of the liver.5-7 Precise evaluations of donor liver volume are important in order to prevent unexpected hepatic insufficiency and to evaluate normal liver rege...

Posttransplantation lymphoproliferative disease (PTLD) is a major complication of current clinical transplantation regimens. The lack of a reproducible large-animal model of PTLD has limited progress in understanding the pathogenesis of and in developing therapy for this clinically important disease. This study found a high incidence of PTLD in miniature swine undergoing allogeneic hematopoietic stem cell transplantation and characterized this disease in swine. Two days before allogeneic peripheral blood stem cell transplantation, miniature swine were conditioned with thymic irradiation and in vivo T-cell depletion. Animals received cyclosporine daily beginning 1 day before transplantation and continuing for 30 to 60 days. Flow cytometry and histologic examination were performed to determine the cell type involved in lymphoproliferation. Polymerase chain reaction was developed to detect and determine the level of porcine gammaherpesvirus in involved lymph node tissue. PTLD in swine is morphologically and histologically similar to that observed in human allograft recipients. Nine of 21 animals developed a B-cell lymphoproliferation involving peripheral blood (9 of 9), tonsils, and lymph nodes (7 of 9) from 21 to 48 days after transplantation. Six of 9 animals died of IntroductionOur laboratory has been successful in developing protocols for establishing mixed chimerism and tolerance across major histocompatibility complex (MHC) barriers in miniature swine without the use of whole-body irradiation (WBI). 1 In one of our protocols developed for this purpose we have observed a high incidence of posttransplantation lymphoproliferative disorder (PTLD). Because of the importance of PTLD clinically, we have attempted to characterize this phenomenon in the miniature swine model.The development of lymphoid neoplasms in allograft recipients receiving immunosuppressive therapy has been recognized as a major complication of solid organ and bone marrow transplantation for over 30 years. 2,3 PTLD and acquired immunodeficiency syndrome (AIDS)-associated B-cell lymphoma are serious and often lethal complications of immunosuppression. The majority of neoplasms involved in PTLD, including those lacking surface immunoglobulin expression, are of B-cell origin. 4,5 A strong correlation has been reported between B-cell neoplasms developing in immunosuppressed patients and the presence of the Blymphotropic gammaherpesvirus Epstein-Barr virus (EBV). 6 In humans, PTLD is thought to represent a spectrum of EBV-driven lymphoid proliferations ranging in histologic appearance from a reactive polymorphic expansion of EBV-infected lymphocytes to monoclonal B-cell lymphomas. 7 Studies of patients who developed PTLD have implicated several risk factors, including T-cell depletion and the degree of immunosuppression; however, the pathogenesis of PTLD is not completely understood. 8,9 The lack of a reproducible large-animal model of PTLD has limited progress in understanding the pathogenesis of and in developing therapy for this clinically import...