Positive effects of anti-T-cell monoclonal antibodies on rat allograft survival.
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Biomedical subjects
Publications and source records attributed to K Claesson.
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Experimental and clinical aspects of organ allograft rejection were studied. The grafts of ten patients subjected to transplantectomy due to irreversible rejection or viral infection were investigated with immunohistochemistry. T lymphocytes were abundant in the cellular infiltrates of the rejected grafts and cells with 'helper/inducer' phenotype were more numerous than cells with 'suppressor/cytotoxic' phenotype. The expression of HLA-DR antigens was found to differ from that of HLA-DQ antigens in healthy human kidneys as well as in infected or rejected kidney grafts. HLA-DR but not -DQ antigens were thus detected in proximal tubular cells and increased during rejection or infection. Serum levels of interferon were found to be related to the occurrence of clinical signs of rejection or viral infection in renal transplant patients. Class II MHC antigen expression and cellular infiltrates were immunohistochemically characterized in untreated rejecting rat kidney grafts and were compared to the reactions of syngeneic renal grafts in the same model. The infiltrates of the syngeneic grafts were smaller and occurred later than those of the allografts and were dominated by cells with the 'helper/inducer' T cell phenotype. The number of class II antigen expressing renal tubules was markedly increased in allogeneic grafts and, to a lesser extent, also in syngeneic grafts. The effects of different monoclonal T cell antibodies were investigated in a rat heart allograft model. A 'pan' T cell antibody and a 'suppressor/cytotoxic' T cell antibody significantly prolonged graft survival and caused expression of class II antigen as well as of T cell 'suppressor/cytotoxic' antigen on graft parenchymal cells. Permanent survival of heart grafts could be achieved after induction with antithymocyte globulin. Grafts functioning for more than eight months were found to have myocardial fibrosis, intimal thickening and fibrosis of vessels, mild lymphocyte infiltration and increased class II antigen expression. The changes observed were similar to those seen in chronic rejection.
Twenty patients, cadaveric renal transplant recipients, were retrospectively analysed for serum levels of deoxythymidine kinase. Special reference was made to the thymidine kinase level in relation to rejection, and viral infection. Seven of the patients experienced clinically suspected cytomegalovirus infection. All these patients had elevated levels of serum thymidine kinase during the period of clinical disease. Usually the thymidine kinase level parallelled the severity of the disease. All patients with irreversible rejection had increased levels of serum thymidine kinase, but normally not as high, as seen in patients with severe cytomegalovirus infection. There was also some correlation between clinically suspected rejection, that lead to rejection treatment, and moderate increase in thymidine kinase. However, not all rejection episodes were accompanied by a thymidine kinase increase. Serum thymidine kinase was analysed and compared in patients with self-healing cytomegalovirus disease, and those treated with phosphonoformate. A rapid decline in thymidine kinase level was found in connection with successful antiviral therapy, when compared to the decline in untreated patients. Some bone marrow transplanted patients were also included in this analysis.
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In a rat kidney transplantation model, DA kidneys were transplanted into Lewis rats. Syngeneic Lewis transplantations were studied as controls. Histologic evaluation was made, and immunohistochemical staining with a single-staining peroxidase-antiperoxidase technique on frozen sections was performed after 2, 4, 6, and 8 days. Antibodies for Ia antigen (Ox 6), 'suppressor/cytotoxic' cells (Ox 8), pan-T cells (W 3/13), and 'helper/inducer' cells (W 3/25) were used. Allogeneic grafts were almost completely rejected in 8 days. Syngeneic grafts also showed lymphocyte infiltrates, somewhat later than allogeneic ones, but were not rejected. In these infiltrates W 3/25-positive cells dominated, being even more numerous than W 3/13-positive cells. Relatively fewer Ox 8-positive cells were seen in the infiltrates of syngeneic than in allogeneic transplants. Infiltrates occurred later in the renal medulla than in the cortex. Perivascular infiltrates with cells of all investigated phenotypes were seen earlier in allogeneic grafts than in syngeneic ones. All tubular cells within one renal tubule appeared either Ox 6-positive or -negative. With time, all tubules in the allogeneic transplants became Ox 6-positive. Some increase of Ox 6-positive tubules was also seen in syngeneic transplants.
Ileal conduit urinary diversion was performed with an antireflux technique, with nippling of the ureters into the segment, in 63 patients. The patients were then followed up for 52 +/- 25 months concerning urographic findings, infections and kidney function. Ureteroileal stenosis developed in 3 of 122 ureters and was surgically corrected. Roentgenologic examination for ureteral reflux was performed about a year postoperatively, and pressure measurements were made in the ileal segment. Reflux of contrast medium was seen in 48 ureters at pressure 51 +/- 30 mm Hg. When no reflux was seen, the maximum infusion pressure was 62 +/- 34 mm Hg. The basal pressure (preceding contrast infusion) was 24 +/- 29 mm Hg. Regular contraction waves with pressure rise in the ileal segment were registered, with duration 10-30 seconds. The study showed no connection between ureteral reflux and pressure in the ileal segment. Complications associated with the antireflux operating technique were few.
Sera collected from a majority (15/16) of recipients of renal transplants occasionally contained low, but significant, levels of antiviral activity, maximally corresponding to 25-50 units of interferon-alpha per milliliter of serum in a bioassay. The exception was the only transplanted patient with a known cytomegalovirus infection, who demonstrated persistent high levels of antiviral activity corresponding to 200-400 interferon units/ml. Only the latter antiviral activity was sufficiently high for a partial characterization. It was pH 2 labile, did not have antigenic properties of interferon-alpha or beta, and may correspond to the lymphokine interferon-gamma. In consecutive serum samples from individual patients, the peaks of the antiviral activity occurred preponderantly in connection with clinical signs and consequent treatment of graft rejections. Interferon may, therefore, be a useful marker (at the serum level) of incipient graft rejection, and of certain viral infections, at least, provided that a more rapid sensitive and precise assay of this lymphokine is developed.
This communication describes an immunohistochemical analysis of rejected human renal allografts. T-lymphocyte subsets were identified in frozen tissue sections, by Leu 1 (anti-'pan' T lymphocytes), Leu 2a (anti-'cytotoxic/suppressor' T cells), and Leu 3a (anti-'helper/inducer' T cells) monoclonal antibodies. In addition, HLA-DR-positive cells were identified by simultaneous labelling with heterologous anti-HLA-DR antibodies. T cells dominated the cellular infiltrates in acute cellular rejection. Leu-3a-positive cells were more numerous than Leu-2a-positive cells. The Leu-3a-positive cells usually appeared in clusters, whereas the Leu-2a-positive cells appeared scattered in the tissue. HLA-DR-positive non-T cells were found within clusters of T 'helper/inducer' cells. The cell pattern shares many features with the findings in delayed-type hypersensitivity reactions.
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