The effect of intrahepatic islet isografts on liver integrity following heterotopic auxiliary liver isotransplantation in rats.
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Biomedical subjects
Publications and source records attributed to H Bitter-Suermann.
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We report the time course of rejections in 110 patients of first cadaver kidney grafts entered into a randomized controlled trial of induction ALG vs continuous IV CyA, with both groups receiving Aza for 30 days and Pred for 3 months. There was no difference in 1-year graft or patient survival in the two induction regimens. Despite a slight delay in time to first rejection, the number, severity, and outcome of rejections were the same in both. Fifty percent of patients never had a rejection, and 80% of these were on CyA monotherapy at 1 year vs only 22% in patients with rejections. Thirty-five percent had a rejection in the first month, and one fourth of these had a repeat in the second month. The risk of graft loss was 10% with a first, 38% with a second, and 50% with a third rejection. First rejections occurring after 30 days rarely caused graft loss and rejection after 90 days proved to be unusual.
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A total of 278 orthotopic rat liver grafts, without arterialization, were performed, in an attempt to determine which of the individual components of UW solution are essential. Livers were preserved by in situ flushing and cold storage with the following results: 56% of rats survived for 1 week after 9 hr of preservation with UW solution as compared with 44% using Marshall solution, and 10% using Collins solution. Having established LD 50 for UW solution, we then omitted its components one at a time and found that omission of HES, raffinose, allopurinol, adenosine, phosphate buffer, or MgSO4 did not change survival after 9 hr of preservation. Omission of lactobionate, glutathione, and dexamethasone, respectively, resulted in decreased survival, whereas elimination of insulin surprisingly increased survival. In ensuing dose-response studies, the concentrations of lactobionate, glutahione, dexamethasone in UW solution proved to be optimal. Finally, livers were preserved with a solution containing only lactobionate, glutathione, dexamethasone, raffinose, and phosphate buffer, resulting in 53% animal survival, as compared with 56% for the unchanged UW solution. We conclude that UW solution can be simplified without loss of effectiveness in this model.
The mechanisms by which cold preservation solutions exert their protective effects are only partially understood. The consequences of mixing different solutions, with presumably different modes of action, may be additive and beneficial or may be deleterious. It is commonplace in clinical liver preservation to use Ringer's lactate (RL), Eurocollins (EC), and University of Wisconsin (UW) solution in sequence for washout of blood, precooling, and cold storage of the organ. In this study, 114 Sprague Dawley rats received orthotopic liver transplants that were flushed in various sequences with RL, EC, and UW solutions. One-week animal survival served as the criterion of preservation success. The results demonstrated that liver preservation with UW solution alone is significantly superior (P less than 0.01) to any combination of RL, EC, and UW solutions and may explain some of the instances of primary nonfunction in clinical liver transplantation.
Between 1981-87, 48 HLA identical sibling graft recipients were allocated to one of three treatment groups: Group I-15 patients Aza and Pred; Group II-12 CyA alone; Group III-21 CyA and steroids. Only one patient died from a fatal hereditary disease. Graft survival was 100% at one year in all groups and at three years was 86% for Aza, 94% for CyA alone and 100% for CyA and steroids. Rejection episodes occurred in 50% of Aza patients versus 18% in the CyA groups. However 55% of CyA patients require anti-hypertensives versus 20% of Aza recipients, and 12% of CyA patients were switched because of drug toxicity. In a previous study of 36 Aza treated A-matched patients, five of eight losses occurred after the first 5 years--most related to long term effects of immunosuppression. We may have to wait for longer follow-up before drawing conclusions regarding the use of CyA in identically matched living related recipients.
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The results of 120 LRD kidney grafts, 49 HLA identical and 71 haploidentical, performed between 1981 and 1987 during the CyA era have been analyzed. The reduction in the incidence of rejection in diploidenticals with CyA vs AZA did not increase short- or long-term graft survival but was accompanied by worse kidney function and a greater need for antihypertensives. CyA did improve the results in haploidentical recipients over our historical experience, although prior sensitization was still a major hazard in this group.
Results in 355 Cs-treated renal graft recipients have been analyzed. The majority of graft losses occurred early. Prior sensitization and repeat grafts were clear-cut early risks for cadaver recipients but not live-related donor grafts. In neither group was presensitization clearly a risk factor for late losses, although repeat grafts were much more at risk late. The majority of late losses was due not to chronic rejection but to deaths from cardiovascular disease and cancer, and a surprisingly high number from noncompliance.
Repeat cadaver kidney transplantation using azathioprine immunosuppression carried a higher risk of graft loss than primary transplants. We analyzed the results of repeat cadaver kidney grafting with cyclosporine A immunosuppression. A total of 33 cyclosporine A-treated patients received the second kidney transplant at varying intervals after failure of the first transplant. Graft survival at 1 year was 66 per cent. A concurrent group of 189 cyclosporine A-treated first cadaver kidney recipients had a 1-year graft survival rate of 75 per cent, although this better result was not statistically significant (p greater than or equal to 0.25). A historical group of 31 azathioprine-treated second graft recipients had a significantly worse 1-year graft survival rate of 45 per cent compared to the cyclosporine A second graft group (p less than 0.1). Patient age, sex, early first graft loss, interval between transplants and the presence of panel reactive antibodies were not factors in predicting second graft outcome. A complete DR mismatch appeared to worsen the second transplant survival. These findings indicate that early graft survival of cyclosporine A-treated repeat cadaveric transplants is acceptable and is better than azathioprine-treated first or second grafts.
The results presented in this report demonstrate that T cells, isolated from AGUS rats bearing long-term (WAG X AGUS)F1 spleen allografts adoptively transferred to irradiated AGUS recipients could not mediate the rejection of WAG hearts but rejected PVG. A hearts in acute fashion. Further, unresponsive T cells were able to suppress the capacity of adoptively transferred (40 X 10(6) normal T cells to reject WAG but not PVG.A heart allografts. We also studied the role of W3/25+ and OX8+ T cells subsets in the maintenance of unresponsiveness. Isolated W3/25+ or OX8+ unresponsive T cells were not able to mediate acute rejection, but were less effective in prolonging WAG allograft survival than the unresponsive whole T cell population, suggesting that both W3/25+ Ts1 and OX8+ Ts2 subsets were required for effective suppression in vivo. When, however, unresponsive W3/25+ T cells were infused simultaneously with normal OX8+ T cells, they could produce indefinite survival of WAG heart allografts. These results indicate that the unresponsive state induced by (WAG X AGUS)F1 spleen allografts transplanted to AGUS rats is maintained by the interaction of W3/25+ T suppressor/inducer and OX8+ T suppressor/effector cells.
Heterotopic (WAG x AGUS)F1 spleen allografts survive indefinitely when transplanted to normal AGUS recipients and induce long-term donor-specific unresponsiveness. In this report, we have examined the immune reactivity of spleen graft recipients soon after transplantation, in an attempt to define the immunological mechanisms responsible for the induction of donor-specific unresponsiveness. Unresponsiveness develops as early as one week after splenic transplantation. T cells obtained from the recipient lymph node and spleen exhibit reduced mixed lymphocyte reaction responses to donor (WAG) but respond normally to third-party (PVG) stimulators. In contrast, T cells obtained from the spleen graft are unresponsive to both donor and third-party stimulators. Donor specific T suppressor cells (Ts) appear in the recipient's lymph node and spleen by one week posttransplantation--however, at this time antigen nonspecific suppressor cells predominate in the spleen graft. Only minimal cytotoxic T cell activity could be detected in the spleen graft, with the host spleen and lymph nodes being devoid of cytotoxic T lymphocytes. Sera obtained one or two weeks following splenic transplantation did not contain cytotoxic alloantibodies, and only a very weak response could be detected at one month. These data demonstrate that the unresponsiveness associated with the spontaneous acceptance of spleen allografts is correlated with the early induction of antigen specific Ts in recipient lymphoid tissue and the presence of nonspecific suppressor cells at the graft site.
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