Biomedical subjects
Publications and source records attributed to G Steinhoff.
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The expression of leucocyte adhesion facilitating molecules on endothelia is a major stimulus for tissue inflammation and cell infiltration. Recently, specific receptor ligands have been identified that mediate cellular adhesion of lymphocytes or monocytes. In the present study, sequential changes in the expression of immune adhesion receptors (LFA-1, CD2) and their ligand molecules (ICAM-1, LFA-3) were studied in heart allografts during rejection. Consecutive endomyocardial biopsies (n = 157; d.3-1013) of 16 heart transplanted patients were studied using monoclonal antibodies and standard immunohistology. In biopsies that showed no rejection, immune adhesion molecules (ICAM-1) were weakly expressed on a few endothelial cells. ICAM-1 was induced on blood vessel and capillary endothelia during rejection. After treatment, expression declined, as did the clearance of infiltrates. Occasionally, ICAM-1 persisted on capillaries compared with class II MHC expression. Weak LFA-3 induction on endothelia was observed in acute rejection, similar to ICAM-1, however LFA-3 expression was more restricted. Infiltrating lymphocytes expressed the adhesion receptor molecules LFA-1 and/or CD2. The variability of expression of ICAM-1 and FA-3 ligand molecules was related to the inflammatory changes in the graft during acute rejection. It is likely that the induction of adhesion ligand molecules in tissue is regulated by systemic and local release of cytokines, and is an initiating step in graft infiltration. The demonstration of immune adhesion-molecule induction in heart graft rejection may also be applicable to inflammatory heart disease in viral myocarditis.
Forty-one endomyocardial biopsies of the right interventricular septum have been investigated in 24 immunosuppressed patients after orthotopic heart transplantation. Monoclonal antibodies 27E10, 25F9, and RM3/1, which react with different macrophage phenotypes, and antisera MRP-8 and MRP-14, specific for proteins expressed on endothelial and monocyte cell surfaces in inflammation as well as markers for CD4+ and CD8+ T-lymphocytes, were employed in an indirect immunoperoxidase staining technique. This methodology permits more physiological recognition of the inflammatory process within the myocardium. It was possible to verify and to distinguish acute early, late and down-regulatory stages of inflammation in 33 biopsies (80%). No evidence of inflammation was found in seven biopsies (17%). Conventional histopathology with haematoxylin-eosin and Masson's trichrome was performed simultaneously, and demonstrated inflammation to be present in 23 of 41 biopsies (56%). An important findings is that CD4+ and CD8+ lymphocytes were absent in 15 of 41 specimens (37%) although there was inflammation proven by the presence of different macrophage phenotypes. The results indicate the necessity of long-term serial investigations of the physiological role of specific inflammatory macrophage phenotypes during the rejection process. It is concluded that the phenotyping of macrophage and endothelial cell differentiation antigens offers a sensitive approach to assess diagnosis of myocardial inflammation as a consequence of ongoing rejection in cardiac allografts.
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Liver transplantation is performed successfully across major HLA differences between donor and recipient. This may be influenced by the organ specific expression of major histocompatibility complex (MHC) molecules which determine the local immune reactivity and rejection response. The tissue expression of MHC molecules on parenchymal and infiltrating cells has been studied in transplanted human liver using monoclonal antibodies and immunohistological methods. A strong induction of class I (HLA-A,B,C; beta 2-microglobulin) and class II (HLA-DR,DQ,DP) MHC antigens was demonstrated on hepatocytes, bile duct epithelium and endothelial cells during rejection episodes and viral and bacterial infections. The massive induction of donor antigens on hepatocytes, bile ducts and endothelia forms part of, and may also augment, the rejection response. During quiescent states without infection or rejection after transplantation, however, a rather restricted expression of class I and class II donor MHC antigens is present. In addition, the donor Kupffer cells and interstitial dendritic cells are gradually replaced by recipient accessory cells expressing self-MHC molecules. The changes in antigen density and distribution of donor MHC alloantigens as the replacement of accessory cells capable of presenting antigens to T-lymphocytes may influence the course of immune reactivity and the rejection response in the liver. This may partly explain the favourable clinical course long after transplantation. Preliminary clinical investigations of the effect of HLA matching have shown a dualistic effect of the matching of class I or class II HLA antigens. The role of HLA matching in liver transplants in large clinical studies, with specific immunological testing however, remains to be investigated. This may lead to prospective HLA matching with wider organ availability and improved preservation time in the future.(ABSTRACT TRUNCATED AT 250 WORDS)
The regulation of expression of adhesion molecules in human liver grafts in the course of rejection and inflammatory reactions was studied. The tissue distribution of adhesion receptor molecules and ligand molecules in graft biopsies taken during complications was compared to that in normal liver and reference biopsies taken at the time of transplantation.
The effect of single and repeated treatment of liver allograft rejection using an anti-CD3 monoclonal antibody (FN18) was studied in a rhesus monkey model. Eight RhLA-mismatched monkeys received initial postoperative immunosuppression with CsA/prednisolone for 28 days. After cessation, acute rejection occurred in all animals (days 28-50). Control animals (n = 3) receiving no rejection treatment developed a chronic progressive rejection and died at days 112-160. In the animals treated with FN18 (n = 5), the first acute rejection was successfully reversed. T lymphocytes were cleared from the peripheral blood and the graft. Increased class I and class II MHC-antigens on hepatocytes were reduced to normal levels within 5 days of treatment. The second rejection treatment remained ineffective in two animals with antiidiotypic antibodies to FN18 but was successful in two animals with a low antimouse response. These four animals survived 160-509 days. The results have a number of implications regarding the course of untreated rejection in human liver transplant recipients and repetitive rejection treatment with monoclonal antibodies.
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A model of rejection and regeneration of peripheral nerve allografts in rats is presented. A 2.5-cm segment of 28 right sciatic nerves was transplanted orthotopically from LEW.1W to DA and from DA to LEW.1W. With a microsurgical technique, proximal and distal coaptations were performed. In an autologous control group the same surgical procedure was applied. Evaluation included clinical estimation of motor recovery and macroscopic appearance of the graft, electrophysiological examination, conventional histology, and immunohistology. The latter concentrated on demonstration of monomorphic and polymorphic determinants of MHC class I and II antigens and of macrophages. By functional, electrophysiological, and histological parameters it was demonstrated that after rejection a certain degree of regeneration took place in the allografts. Both rejection and subsequent regeneration were studied in detail by immunohistology. During the course of Wallerian degeneration MHC class I expression on myelin sheaths could be demonstrated. When the rejection response occurred, additional MHC class II expression on myelin sheaths and on vascular endothelial was observed. Recipient specific class I-positive macrophages were infiltrating the graft from the epineurium and the coaptation sites, and were later present at the sites of myelin degradation. At 6 weeks postoperatively donor-specific MHC products were no longer detectable, but recipient-specific Schwann cells were present in the allograft tissue. We conclude that a rejection response renders a peripheral nerve allograft acellular but does not destroy the nerve architecture, still enabling it to function as an axon conduit. The regeneration in the rejected allograft however lacks the positive neurotropic and -trophic influence physiologically provided by viable Schwann cells.
The existing follow-up standard for breast cancer patients has been reviewed by a representative trial involving 1,004 curatively treated patients, who underwent surgery between 1977 and 1987. The objective of the study has been to establish whether intensive diagnostics of recurrences and metastases will lead, as a result of the follow-up, to life prolongation or improvement of life quality, and which methods will be adequate to achieve this goal. The analysis has shown that metastases are recognized only insignificantly earlier, and that improvement of survival is not achieved. The results of the trial have led to a recommendation for an effective follow-up programme for breast cancer patients, with emphasis on subtle case history data and exact clinical investigations.
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The valid follow-up standard for mammary carcinoma was checked by means of a retrospective study with 1,004 curatively treated patients operated between 1977 and 1987. The aim of this study was to find out whether intensive diagnostics of recurrences and metastases resulted in early detection and prolongation of life and/or improvement of life quality. Evaluation of two groups (early detection and treatment as compared to late detection and treatment) showed that diagnosis was only slightly earlier (1,2 months) which did not lead to longer life. These results gave rise to recommendations for an efficient follow-up regime for patients with mammary carcinoma. Exact case history and clinical examinations are more important for asymptomatic patients than intensive diagnostics:
The relationship between adenine nucleotide metabolism and ischemic damage was studied in human liver. Thirty transplanted grafts were divided into two groups according to their functional outcome. Cellular adenine nucleotide levels were assayed by high-performance liquid chromatography. During cold ischemia, the adenosine triphosphate (ATP) level was not correlated with graft function, but two grafts with low total adenine nucleotides (TAN) levels showed poor function after transplantation. After recirculation, the ATP level showed good recovery in grafts that functioned satisfactorily (n = 24, 5.47 +/- 1.51 mumol/g dry weight), but remained low in poorly functioning grafts (n = 6, 3.30 +/- 1.68 mumol/g dry weight) (P less than 0.01). The level of recovery of ATP was inversely related to the period of warm ischemia during implantation (P less than 0.01). Bile production, used as a parameter of initial function, was observed shortly after implantation in 17 of 24 grafts that functioned satisfactorily, but in only 1 of 6 poorly functioning grafts. It is concluded that loss of adenine nucleotides and lack of bile production during transplantation are good markers of damaged grafts in human liver transplantation.