Immunosuppression with FK506 in rat arterial allografts: fate of allogeneic endothelial cells.
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PURPOSE: This study clarified the efficacy of low-dose FK506 and the possibility of discontinuing the use of FK506. METHODS: Fresh carotid arteries were allografted from ACI rats to Lewis rats. FK506 (0.2 mg/kg/day) was given intramuscularly from day 3 after transplantation until the rats were killed (group III), or it was given for 4 weeks and then discontinued (group IV). Isogeneic (group I) and allogeneic (group II) models served as untreated control groups. Grafts were harvested on days 0, 1, 3, 7, 14, 21, 28, 70, and 105 after transplantation. Histological evaluation and measurement of the endothelial cell (EC)-covered area were performed by means of scanning electron microscopy. RESULTS: In group I, ECs were denuded immediately after transplantation and subsequently regenerated within 2 weeks. In group II, after denudation and regeneration of ECs, massive leukocyte adhesion and subsequent destruction of regenerated ECs, followed by intimal hyperplasia, were observed. In group III, FK506 suppressed rejection almost completely, without intimal hyperplasia. In group IV, severe rejection and denudation of regenerated intima appeared 2 weeks after the use of FK506 ended. CONCLUSION: The denudation and regeneration of ECs may play an important role in the process of rejection and graft performance. FK506 proved to be successful in rat arterial allografting, and ECs of donor origin could survive on the allograft as long as FK506 was effective; however, cessation of the use of FK506 resulted in severe destruction of intima. To prevent allograft failure, long-term administration of an immunosuppressant is essential. (+info)
Enhancement of graft-versus-tumor activity and graft-versus-host disease by pretransplant immunization of allogeneic bone marrow donors with a recipient-derived tumor cell vaccine.
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Allogeneic bone marrow transplantation (BMT) can be accompanied by a beneficial T cell-mediated antitumor immune response known as graft-versus-tumor (GVT) activity. However, BMT donor T cells are not exposed to target antigens of GVT activity until transfer to the host, where tumor antigen presentation may be suboptimal. This study tested in a murine model the hypothesis that immunization of MHC-matched allogeneic donors with a recipient-derived tumor cell vaccine would substantially increase GVT activity and extend survival of BMT recipients with preexisting micrometastatic tumor. C3H.SW and C57BL/10 mice were immunized against a C57BL/6-derived fibrosarcoma or leukemia, and they were used as BMT donors. Recipients were H-2-matched, minor histocompatibility antigen-mismatched C57BL/6 mice with previously established micrometastatic tumors. Donor immunization led to a significant increase in GVT activity that was T cell dependent and cell dose dependent. In some settings, donor immunization also prolonged survival of recipients with preexisting micrometastatic tumors. However, donor immunization significantly increased the incidence of fatal graft-versus-host disease such that long-term survival was uncommon. In vitro cytotoxicity assays indicated that donor immunization induced both tumor-selective and alloreactive cytolytic T-cell populations. In vivo cross-protection assays showed that a substantial portion of the GVT effect was mediated by alloreactive cells not specific for the immunizing tumor. In conclusion, immunization of allogeneic BMT donors with a recipient-derived whole tumor cell vaccine substantially increases GVT activity but also exacerbates graft-versus-host disease. (+info)
Impact of cyclosporine and methylprednisolone dose used for prophylaxis and therapy of graft-versus-host disease on survival and relapse after allogeneic bone marrow transplantation.
(67/9074)
In order to determine whether doses of cyclosporine and methylprednisolone used for prophylaxis and therapy of acute graft-versus-host disease (GVHD) have any influence on relapse and survival following allogeneic bone marrow transplantation (BMT), we studied 176 adult patients with hematologic malignancies, who underwent a first allogeneic transplant from an HLA-identical sibling donor. Two methods of management of acute GVHD used in two different centers were compared: group I included 62 patients who had 'standard' management of GVHD including prophylaxis with 1-3 mg/kg/day of cyclosporine and treatment with 2 mg/kg/day of methylprednisolone when acute GVHD developed; group II included 114 patients who received 'intensive' management of GVHD including prophylaxis with 5 mg/kg/day of cyclosporine and treatment with high-dose methylprednisolone (8-20 mg/kg/day for 3 days) at the onset of GVHD. The overall incidence of GVHD was the same in both groups. However, acute GVHD was more severe in group I than in group II (P < 0.0001), with consequently less resolution of GVHD after treatment in group I (61%) than in group II (80%) (P = 0.06). Overall survival and disease-free survival (DFS) did not differ between the two groups. However, actuarial risk of disease relapse was significantly higher in group II than in group I (36% vs 17%, P = 0.02). In a multivariate analysis taking into account known factors influencing GVHD and relapse, only type of GVHD management and age were significantly predictive for the occurrence of GVHD, while only type of GVHD management and pathology other than chronic myeloid leukemia (CML) were predictive for relapse. This study demonstrates that intensity of GVHD prophylaxis and therapy can influence the graft-versus-leukemia effect by decreasing severity of GVHD but at the price of increasing relapse rate post transplant. (+info)
Donor hematopoietic progenitor cells in nonmyeloablated rat recipients of allogeneic bone marrow and liver grafts.
(68/9074)
BACKGROUND: Although the persistence of multilineage microchimerism in recipients of long-surviving organ transplants implies engraftment of migratory pluripotent donor stem cells, the ultimate localization in the recipient of these cells has not been determined in any species. METHODS: Progenitor cells were demonstrated in the bone marrow and nonparenchymal liver cells of naive rats and in Brown Norway (BN) recipients of Lewis (LEW) allografts by semiquantitative colony-forming unit in culture (CFU-C) assays. The LEW allografts of bone marrow cells (BMC) (2.5x10(8)), orthotopic livers, or heterotopic hearts (abdominal site) were transplanted under a 2-week course of daily tacrolimus, with additional single doses on days 20 and 27. Donor CFU-C colonies were distinguished from recipient colonies in the allografts and recipient bone marrow with a donor-specific MHC class II monoclonal antibody. The proportions of donor and recipient colonies were estimated from a standard curve created by LEW and BN bone marrow mixtures of known concentrations. RESULTS: After the BMC infusions, 5-10% of the CFU-C in the bone marrow of BN recipients were of the LEW phenotype at 14, 30, and 60 days after transplantation. At 100 days, however, donor CFU-C could no longer be found at this site. The pattern of LEW CFU-C in the bone marrow of BN liver recipients up to 60 days was similar to that in recipients of 2.5x10(8) BMC, although the donor colonies were only 1/20 to 1/200 as numerous. This was expected, because the progenitor cells in the passenger leukocytes of a single liver are equivalent to those in 1-5x10(6) BMC. Using a liquid CFU-C assay, donor progenitor cells were demonstrated among the nonparenchymal cells of liver allografts up to 100 days. In contrast, after heart transplantation, donor CFU-C could not be identified in the recipient bone marrow, even at 14 days. CONCLUSION: effective immunosuppression, allogeneic hematopoietic progenitors compete effectively with host cells for initial engraftment in the bone marrow of noncytoablated recipients, but disappear from this location between 60 and 100 days after transplantation, coincident with the shift of donor leukocyte chimerism from the lymphoid to the nonlymphoid compartment that we previously have observed in this model. It is possible that the syngeneic parenchymal environment of the liver allografts constitutes a privileged site for persistent progenitor donor cells. (+info)
Mechanisms of induction of renal allograft tolerance in CD45RB-treated mice.
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BACKGROUND: Rejection is the most significant problem in the field of transplantation. The current goal of transplant immunology is to develop better immunotherapeutic protocols that are aimed at specifically suppressing alloreactivity and preserving an otherwise intact immune system. We have previously shown that mice will accept renal allografts indefinitely with normal renal function after two injections of a monoclonal antibody to the CD45RB protein. Furthermore, this antibody will reverse acute rejection when therapy is delayed until day 4 and will still induce tolerance. The mechanisms of this therapeutic benefit are not known. METHODS: BALB/C mice were used as recipients of major multiple histocompatibility complex-mismatched kidneys using C57BL/6 as donors. Immunoperoxidase microscopy and Northern blots for cytokine gene expression were used to study the renal allografts. Fluorescence-activated cell sorter (FACS) analyses of peripheral blood lymphocytes were performed. Phosphotyrosine peptide phosphatase assays were performed on splenic lymphocyte membranes. RESULTS: A CD45RB monoclonal antibody (MB23G2) induced tolerance and partially depletes peripheral blood lymphocytes. A therapeutically ineffective CD45RB monoclonal antibody (MB4B4) merely coated the circulating lymphocytes. Furthermore, MB23G2 stimulated more tyrosine phosphatase activity than MB4B4 in mouse T-cell membranes. CONCLUSIONS: The clearance of peripheral blood lymphocyte populations and stimulation of protein tyrosine phosphatase activity may be important in the mechanism of tolerance induction by CD45RB therapy, which may be clinically relevant in the therapy of organ rejection in humans. (+info)
The pathology of bone allograft.
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We analysed the histological findings in 1146 osteoarthritic femoral heads which would have been considered suitable for bone-bank donation to determine whether pathological lesions, other than osteoarthritis, were present. We found that 91 femoral heads (8%) showed evidence of disease. The most common conditions noted were chondrocalcinosis (63 cases), avascular necrosis (13), osteomas (6) and malignant tumours (one case of low-grade chondrosarcoma and two of well-differentiated lymphocytic lymphoma). There were two with metabolic bone disease (Paget's disease and hyperparathyroid bone disease) and four with inflammatory (rheumatoid-like) arthritis. Our findings indicate that occult pathological conditions are common and it is recommended that histological examination of this regularly used source of bone allograft should be included as part of the screening protocol for bone-bank collection. (+info)
Histopathology of retrieved allografts of the femoral head.
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From November 1994 to March 1997, we harvested 137 grafts of the femoral head from 125 patients for donation during total hip arthroplasty according to the guidelines of the American Associations of Tissue Banks (AATB) and the European Association of Musculo-Skeletal transplantation (EAMST). In addition to the standards recommended by these authorities, we performed histopathological examination of a core biopsy of the retrieved bone allograft and of the synovium. Of the 137 allografts, 48 (35.0%) fulfilled all criteria and were free for donation; 31 (22.6%) were not regarded as suitable for transplantation because the serological retests at six months were not yet complete and 58 (42.3%) were discarded because of incomplete data. Of those discarded, five showed abnormal histopathological findings; three were highly suspicious of low-grade B-cell lymphoma, one of monoclonal plasmacytosis and the other of non-specific inflammation of bone marrow. However, according to the standards of the AATB or EAMST they all met the criteria and were eligible for transplantation. Our findings indicate that the incidence of abnormal histopathology in these retrieved allografts was 3.6%. Since it is essential to confirm the quality of donor bones in bone banking, we advise that histopathological screening of donor bone should be performed to exclude abnormal allografts. (+info)
Changes in allograft bone irradiated at different temperatures.
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Secondary sterilisation of allograft bone by gamma irradiation is common, but the conditions under which it is performed vary between tissue banks. Some do so at room temperature, others while the bone is frozen. Bone is made brittle by irradiation because of the destruction of collagen alpha chains, probably mediated by free radicals generated from water molecules. Freezing reduces the mobility of water molecules and may therefore decrease the production of free radicals. We found that bone irradiated at -78 degrees C was less brittle and had less collagen damage than when irradiated at room temperature. These findings may have implications for bone-banking. (+info)