Academic surgery and the law: a report from the Committee on Issues of the Association of Academic Surgery, 1978.
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Biomedical subjects
Publications and source records attributed to F T Thomas.
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These studies demonstrate that immune monitoring and individualized modulation of recipient immune reactivity using a quality-controlled preparation of rabbit antithymocyte globulin can improve results of cardiac transplantation. The most valuable assay in individualizing drug doses was the serial measurement of T-cell levels using a complete lymphocyte profile technique and monitoring with phytohemagglutinin to rule out false low T-cell levels. Using this system, the incidence and severity of early rejections were markedly reduced and no grafts were lost to rejection in the first month. The recent first-year graft survival has been about 60%, an improvement largely related to a reduction in early rejection and infection. This technique of immunosuppression appears quite promising for improving the results of future cardiac transplantations.
Immunological monitoring assays are of current value in the management of transplant recipients. These assays allow the pre-transplant quantitation of both donor-recipient histocompatibility and recipient "responder status." In addition, these assays allow the individualization of immunosuppression, permitting a more uniform and effective immunosuppression in the difficult early post-transplant period. Individualized modulation of recipient immune reactivity avoids the documented pitfalls of conventional stereotyped suppression and permits better abrogation of acute rejection responses and lesser rates of serious infections consequent to excessive immune suppression. Immunological monitoring of long-surviving recipients permits early detection of immune reactivity which often culminates in clinical chronic rejection, as well as permits the quantitation of immune facilitory mechanisms (reduced capability to generate anti-donor cytotoxic T cells and/or cellular suppressor mechanisms) that indicate an immune milieu conductive to long-term graft survival. The primary limitations to the more widespread use of immunological monitoring assays at present are the need for more consensual validations of the utility of these assays in different laboratories, more standardization and better controls of techniques, and improvement in the technology of the assays to permit rapid, reproducible, and accurate results with a lesser expenditure of laboratory time and money and greater economy in demands for recipient blood and donor tissue. Finally, immunological monitoring assays are notable for the great promise they offer in terms of immunobiological probes to dissect mechanisms of rejection, mechanisms of graft facilitation, mechanisms of action of immunosuppressive agents, and mechanisms by which empirical technology of recipient pre-treatment may condition the host to better acceptance of an incompatible graft.
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Spotaneous E rosette-forming (T) lymphocytes were monitored in the peripheral blood of rhesus monkeys receiving a 5-day course of rabbit anti-human thymocyte globulin (RATG) after skin allotransplantation. Mean graft survival in RATG-treated recipients was 32.3 +/- 7.6 (SD) days compared with 8.2 +/- 1.7 (SD) days in controls. The percentage and total number of circulating T cells fell precipitously after RATG treatment and recovered slowly. Linear regression analysis showed that the recovery pattern of the total number of circulating T cells, but not the percentage of T cells, was significantly correlated with rejection. Specific antihuman T cell antibody was detected in RATG preparations after extensive absorption with human erythrocytes, platelets, and B lymphoblastoid cells. The cytotoxic titers of B cell-absorbed RATG preparations to human peripheral blood lymphocytes showed a significant correlation with the mean skin allograft survival times obtained in RATG-treated primates. Overall the data suggest that the immunosuppressive potency of RATG in the primate skin graft assay is related in large part to its anti-T cell activity.
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Antibody-dependent cell-mediated cytotoxicity (ADCMC) was studied retrospectively in 20 long-term (1.3-11 years) renal allograft recipients. The serum of all seven patients having persistent proteinuria greater than 1 g/24 hr exhibited positive ADCMC activity to donor lymphocytes. All 11 patients having a negative ADCMC test had normal levels of urinary protein (mean + 0.28 +/- 0.06 (SE) g/24 hr). Two patients had a positive ADCMC test but had normal urinary proteins and no evidence of chronic rejection. In the ADCMC positive group, the mean serum creatinine values were significantly higher and the mean creatinine clearance values were significantly lower than in the ADCMC negative group. There was no significant positive correlation between the presence of ADCMC and the number of HL-A mismatches identified or the response to donor lymphocytes in mixed lymphocyte culture tests in the two groups. Two patients had transplant nephrectomy and histologically showed both glomerular and arterial lesions of chronic rejection. Post-transplant ADCMC activity showed a significant correlation with proteinuria, decreased creatinine clearance, and elevated serum creatinine, and suggests that the chronic rejection syndrome may be related to ADCMC activity in the recipient.