A rabbit model for heterotopic cardiac transplantation.
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Biomedical subjects
Publications and source records attributed to L J Dumble.
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In the murine cardiac model for vascularised transplantation graft function may be monitored by direct palpation, electrocardiography, and graft histology. To assess the merits of these methods, and to measure ischaemic damage, isografts and allografts were examined at regular intervals from 0 to 60 days after grafting. Heart transplants were vascularised from the abdominal great vessels, using microsurgical techniques, with ischaemic times of less than 60 min. Isografts showed no decrease in heart rate over 60 days, as measured by palpation and electrocardiography, but the voltage of the ventricular complex fell progressively over the first 28 days after grafting then remained stable for more than 60 days. The voltage drop was associated with atrophy of myocardial tissue. Allografts in recipients treated with rabbit antimouse antilymphocyte serum were maintained for more than 60 days with little change in palpation rate or recorded heart rate but with significant falls in ventricular complex voltage, reflecting myocardial atrophy and fibrosis. Untreated allografts were rejected in 10-14 days and showed a rapid fall in palpated heart rate, measured heart rate, and ventricular complex voltage. Thus, in this study, palpation of the heart graft gave an accurate measure of the pulse rate and correlated with electrical activity in acutely rejecting grafts, but in long surviving grafts measurement of ventricular complex voltage showed myocardial damage that was not detectable by direct palpation.
The study investigated whether preoperative in vitro sensitivity of lymphocytes from potential renal transplant recipients could identify patients at increased risk of acute rejection following transplantation and immunosuppression with cyclosporine, azathioprine, and prednisolone. Mixed lymphocyte culture responses were measured preoperatively in the presence of methylprednisolone, CsA, and antithymocyte globulin, and without immunosuppressive agents in 50 transfused recipients of primary cadaver renal transplants. Patients were classified as sensitive if all three immunosuppressive agents produced more than 50% inhibition of their MLC responses, and as resistant if one or more agents failed to produce 50% inhibition. All patients received postoperatively a standardized triple immunosuppressive regimen. Acute rejection was confirmed histologically and treated with Pred with or without ATG or monoclonal antibody OKT3. A total of 29 patients (58%) were sensitive and 21 (42%) were resistant; 4 patients were resistant to 3 agents, 5 were resistant to MP and ATG, 6 were resistant to MP and CsA, and 6 were resistant to MP alone. Sensitive and resistant groups did not differ in age, sex, transfusion history, HLA A, B and DR mismatches or duration of follow-up. The resistant group had a higher rate of graft loss from acute rejection (chi 2 = 6.0, d.f. = 1, P less than 0.02), more episodes of acute rejection (chi 2 = 8.7, d.f. = 3, P less than 0.05), and a higher proportion of patients in whom reflux nephropathy was the cause of renal failure (chi 2 = 18.3, d.f. = 1, P less than 0.001). The resistant group also had a higher proportion of highly sensitized patients and higher serum creatinine concentrations than the sensitive group, although the differences did not reach statistical significance. The study indicates that patients at high risk of acute rejection of renal allografts can be identified by a pretransplant in vitro assay, a finding that could influence recipient selection and immunosuppression.
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Isograft studies were performed in the murine model of cardiac transplantation to investigate the morphologic effects of operative ischemia. Primarily vascularized CBA mouse hearts were grafted heterotopically into the recipient CBA mouse's abdomen with standard microsurgical techniques. After ischemia times of 30 and 60 minutes, histologic examination showed minimal myocardial damage, with necrosis or scarring occupying less than 5% of the cross-sectional area of hearts bisected from apex to base after grafts had been removed on the seventh day after transplantation. Maximal ischemic damage was seen at 7 days after transplantation after 120 minutes of ischemia, with more than 30% myocardial necrosis or scarring of myocardial tissue. Isografts performed with ischemia times of less than 60 minutes were followed for more than 100 days. All hearts showed a fine, generalized, perimyocytic fibrosis, which was maximal at 28 days after transplantation and did not progress thereafter. These results will serve as important control measures for future studies in this model because ischemic damage must be considered in examining histologic samples from long-surviving cardiac allografts maintained in immunosuppressed recipients.
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