Treatment of kidney-allograft rejection with cyclosporin A.
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Biomedical subjects
Publications and source records attributed to P J Morris.
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A prospective study of the effect of the route of administration of prophylactic antibiotic on the wound infection rate following gastrointestinal surgery was performed. Patients were randomly allocated to one of three groups: group 1 received no form of antibiotic prophylaxis; group 2 received 1 g of cephradine applied topically to the wound at closure; group 3 received 1 g of cephradine intravenously at induction of anaesthesia and a further intravenous dose of 500 mg 4 h later. Wound infections occurred in 12 of 83 patients in the control group (14.5 per cent), in 6 of the 83 patients in the group who received topical antibiotic (7.2 per cent) and in 3 of the 82 patients who received systemic antibiotics (3.6 per cent). Only the group who received systemic antibiotic showed a statistically significant reduction in the incidence of wound infections compared with the control group (P = 0.03).
Vein allografts were studied in the rat using the major histocompatibility complex-incompatible DA and Lewis inbred strains. Allografts were performed in the Lewis to DA and DA to Lewis combinations, with Lewis to Lewis isografts serving as controls. Vein grafts were performed by interposing a 1 cm length of fresh iliolumbar vein into a defect of the iliac artery, using microsurgical techniques. The grafts were under observation for 18 weeks for (1) patency, (2) gross structural changes, (3) histological changes, and (4) antibody responses. No immunosuppression was used. All grafts remained patient throughout the period of observation, although aneurysm formation was noted in some allografts toward the end of the observation period. Histologically, allografts and isografts were indistinguishable. In the first 2 weeks, they showed patchy areas of necrosis in the vein walls, with subsequent intimal hyperplasia and medial fibrosis. In both strain combinations a lymphocytotoxin response was induced in most animals, the response being particularly strong in the DA to Lewis combination. All cytotoxic activity could be absorbed out using red blood cells, suggesting that the specificity of the antibody was mainly or entirely directed against SD antigens.
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Serum samples from 66 recipients of first cadaver donor renal transplants were screened for cytotoxic antibodies to normal T and B lymphocytes and B lymphocytes from chronic lymphocytic leukaemia patients. In addition, the sera of 44 patients were tested with the B lymphocytes of their respective donors. Donor-specific antibodies were found in 10 of 16 (63%) recipients who had lost their transplant within 2 months, and in 17 of 28 (61%) patients with functioning transplants at 2 months. No correlation was found between the development of B lymphocyte antibodies (either against the panel or the donor) and the onset of an acute rejection episode. In the 17 patients with a successful transplant and donor-specific antibodies, six (35%) had not experienced a rejection episode and another seven patients developed their antibodies after the appearance of the first rejection episode. Thus, our results show that the appearance of donor-specific B lymphocyte antibodies after transplantation is not indicative of graft failure or predictive of acute rejection episodes. However, the common occurrence of such antibodies raises questions concerning the nature of the antigenic stimulus, the specificity of the antibodies, and their role (if any) in transplantation.
Whole antiserum, IgG, and a greater than 99% pure F(ab')2 preparation were compared for their ability to enhance Lewis renal allografts in DA recipients. Despite having unimpaired antigen-binding capacity, the DA anti-Lewis F(ab')2 was virtually ineffective at the highest dose tested, and was calculated to be a minimum of 100 times less effective than whole antibody. The administration of a 10-fold excess of F(ab')2 before an effective dose of IgG did not block the enhancing effect of the latter.
Cyclophosphamide was tested for its interaction with passive enhancement in suppressing the rejection of kidney allografts in the (DA x Lewis)F1 to Lewis rat strain. Dose response studies with cyclophosphamide showed that 10 mg/kg/day for 14 days was necessary for complete suppression of rejection and indefinite graft survival. Doses of 5 and 3.5 mg/kg/day had only a marginal effect on graft function and survival, although the lymphocytotoxin response to the graft was completely or very substantially suppressed by these smaller doses. The use of passive enhancement with cyclophosphamide at the 5- and 3.5-mg/kg/day doses resulted in a favourable interaction with improved graft function and survival. Interestingly, passive enhancement in combination with 5 mg/kg/day of cyclophosphamide resulted in indefinite graft survival only if cyclophosphamide was given for 28 days. If cyclophosphamide was given for 14 days, rejection was suppressed only during the period of cyclophosphamide treatment.
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Lymphoceles occurred in 25 of 115 patients after renal transplantation in the Oxford Unit. Signs of obstruction or pressure were produced in 16 of these 25 patients (15%), while nine were detected on a routine ultrasound scan. The 16 symptomatic lymphoceles were treated successfully by aspiration or surgical fenestration into the peritoneal cavity . Of the possible causes examined, diathermy and division of iliac lymphatics seemed to be the most likely reason for this high incidence. Since a technique of ligating or clipping the iliac lymphatics has been adopted, no lymphoceles have occurred in the subsequent 70 transplants.
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Cyclophosphamide and antilymphocyte serum (ALS) were compared for their ability to suppress renal allograft rejection in the rat. These two agents were chosen since they are generally considered to act on different arms of the immune response, and might therefore complement each other's action. Dose response studies showed that both agents could suppress rejection completely. There were no differences in their ability to suppress the lymphocytotoxic antibody response to the graft and the histological patterns of rejection were similar. There was no evidence that cyclo-phosphamide was more effective in suppressing vascular lesions. The doses of both agents which suppressed the lymphocytotoxic antibody response were substantially lower than those required to suppress graft rejection. When suboptimal doses of the two agents were administered together, the combinations were found to be additive and not synergistic.
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