[Artificial pacemaker implantation].
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Adolescent↗
Biomedical subjects
H Löhr
Publications and source records attributed to H Löhr.
Duration of immunosuppressive therapy in autoimmune hepatitis.
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Adolescent↗
Long-term management and prognosis of autoimmune hepatitis (AIH): a single center experience.
BACKGROUND: Controlled trials have firmly established the need for immunosuppressive therapy in autoimmune hepatitis. However, reports about long-term management and prognosis of the disease are scarce. PATIENTS AND METHODS: We reviewed the charts of 103 consecutive patients with a well-documented long-term course of autoimmune hepatitis who had been carefully managed over a mean observation period of 95 months (12-405 months). RESULTS: Under immunosuppressive therapy 94 patients (91.2%) reached complete remission after a mean treatment duration of 3 +/- 3 months. 28 of the 103 patients (27.2%) were eligible for a trial of treatment withdrawal after a mean treatment duration of 32.2 months (range: 12-81 months). 21 of these patients (75%) had a relapse following treatment withdrawal. 13.6% of patients had intolerance of or severe side effects to azathioprine. There was no increase in tumor risk during a cumulative observation period of 423 patient-years of azathioprine therapy. Corticosteroid side effects occurred mostly during induction therapy, but were usually minor and resolved upon dose reduction. During a cumulative observation period of 842 patient-years no liver related deaths occurred and no patient had to be referred to liver transplantation, even though 30 patients (29.1%) had histological evidence of cirrhosis at presentation. The overall 5- and 10-year survival of patients with autoimmune hepatitis was identical to an age- and sex-matched control population. CONCLUSION: Our study shows that the majority of patients with AIH do achieve a complete remission within 3 months, but require long-term or permanent immunosuppressive therapy that is usually well tolerated. Long-term survival in well-managed patients is excellent.
Adolescent↗
[Synthesis of tumor affinity label Yb-169- and Y-90- porphyrin complexes and animal experimental investigations with various Yb-169-porphyrins].
AIM: It should be shown, that it is possible to insert radioactive isotopes of Yb and Y into some selected porphyrins. Besides, first informations about the biodistribution of Yb-169-por-phyrin-complexes should be obtained. METHODS: Carrier added radioactive isotopes were used for the synthesis of the metal porphyrin complexes. The animal experiments were done with mamma carcinoma bearing mice. The activity of the organs was determined 5 and 24 h after i.v. injection in a well counter. RESULTS: Four Yb-169-porphyrin complexes and Y-90-porphyrin complexes could be synthesized in non-carrier-free form. This was verified by absorption spectra, TLC and HPLC. Depending on the complex, the average tumour/background ratios were between 2 and 20. CONCLUSION: The synthesized radioactive metal-porphyrin complexes showed a clear tumour-affinity which could be used for tumour scintigraphy or perhaps therapy if the synthesis is improved (goal: reduction of carrier, other radionuclides).
Animals↗
Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis.
BACKGROUND/AIMS: Autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis are chronic liver diseases with probable autoimmune background. Overlapping features have been described for primary biliary cirrhosis and autoimmune hepatitis. In contrast, there have been only a few case reports on an overlap of autoimmune hepatitis and primary sclerosing cholangitis. METHODS: We describe three male patients with clinical and histological overlapping features of primary sclerosing cholangitis and autoimmune hepatitis. RESULTS: All initially asymptomatic patients had elevated levels of aminotransferases, alkaline phosphatase, gamma-glutamyltranspeptidase and IgG. Anti-nuclear antibodies and/or smooth muscle antibodies were positive and anti-neutrophil cytoplasmic antibodies were detected in all patients. Retrograde endoscopic cholangiography showed bile-duct strictures characteristic for primary sclerosing cholangitis. Histopathology showed necro-inflammatory activity of portal tracts with bridging necrosis in all patients at the time of first diagnosis. Aminotransferase levels and the necro-inflammatory activity responded well to immunosuppressive treatment. Predominant periductular fibrosis as a typical histopathological feature of primary sclerosing cirrhosis was seen to develop in all patients. Cholestatic serum parameters remained elevated and periductular fibrosis as endoscopic bile duct changes progressed despite immunosuppression. CONCLUSIONS: We suggest that these patients present an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis as they fulfill the diagnostic criteria for both conditions.
Adolescent↗
Posttransfusional, LKM-1-autoantibody-positive hepatitis C virus infection, cryoglobulinemia, and aplastic anemia.
Aplastic anemia is occasionally caused by viral hepatitis, hepatitis C virus being the most important factor. Pathogenetically, decreased bone marrow function, abnormalities of the bone marrow microenvironment, and immune-mediated suppression of hematopoiesis are important. Hepatitis C virus infection is associated with a variety of extrahepatic manifestations including autoimmune features like cryoglobulinemia, Sjögren's syndrome, and autoimmune hepatitis. Here we report the case of a 42-year-old man with aplastic anemia due to posttransfusional hepatitis C virus infection associated with cryoglobulinemia and LKM-1 autoantibodies. Following a triple immunosuppressive therapy, there was a complete reconstitution of the bone marrow. Serum HCV-RNA as well as plus- and minus-stranded HCV-RNA in peripheral blood mononuclear cells (PBMC) were detected before immunosuppressive therapy. After therapy, serum HCV-RNA persisted. Furthermore, PBMC now were positive for plus-stranded RNA only. However, in bone marrow-derived precursor cells we failed to demonstrate HCV molecules after therapy. This would argue for reconstituted PBMC from newly generated uninfected precursor cells. It remains unclear as to whether the autoimmune character of the disease or the hepatitis C virus infection itself have contributed to the pathogenesis of the aplastic anemia.
Adult↗
Parenchymal and nonparenchymal liver cells and their interaction in the local immune response.
Nonparenchymal liver cells (Kupffer cells, sinusoidal endothelial cells, Ito-cells and liver-associated lymphocytes) interact with hepatocytes and with each other by soluble mediators and direct cell-cell contact. The acute phase response is a nonspecific reaction of the organism to trauma, injury or infection and its main constituents the acute phase proteins are produced by hepatocytes. The profile of acute phase protein production is influenced by the local presence of cytokines with IL-6 as the principal regulator. Nonparenchymal cells (Kupffer cells, sinusoidal endothelial cells and Ito-cells) are a source of IL-6 and therefore participate in the generation of acute phase response. The release of IL-10 by Kupffer cells with consecutive down-regulation of IL-6 production may be a mechanism by which resolution of acute phase response is achieved. Still, the mechanisms underlying chronic inflammation remain unclear. Concerning the antigen-specific immune response nonparenchymal liver cells have a number of important functions. They can act as antigen-presenting cells (Kupffer cells) or mediate effector functions (liver associated lymphocytes). Local interaction of nonparenchymal cells with hepatocytes can be mediated by cytokines and/or adhesion molecule expression which again may lead to mutual influence of immunological functions, e.g. TNF-alpha release by Kupffer cells may enhance MHC-II expression on hepatocytes and consequently augment antigen-presenting capacity leading to an improved antigen-specific immune response. Leukocytes are attracted and home to the liver by mechanisms poorly defined because the initial contact between leukocytes and macrovascular endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute-Phase Reaction↗
Significance of IgG and IgM HCV antibody secretion in vitro in patients with chronic hepatitis C: correlation with disease activity and response to interferon-alpha.
Hepatitis C virus antibodies are found in the serum of most patients with chronic hepatitis C. However, the significance of the humoral response is still uncertain. In this study, in vitro IgG and IgM anti-hepatitis C virus secretion by peripheral blood mononuclear cells of patients with chronic hepatitis C was analyzed. Peripheral-blood mononuclear cells from 21 of 36 patients (58.3%) secreted IgG anti-hepatitis C virus in vitro, as demonstrated with anti-hepatitis C virus-specific enzyme immunoassays and recombinant immunoblot assays. Ten of the 36 patients (27.8%) showed both IgG and IgM anti-hepatitis C virus core in vitro. In 9 of these 10 patients, IgM anti-hepatitis C virus was also detected in serum. Patients with in vitro IgM or IgG anti-hepatitis C virus secretion had higher ALT levels in serum than did patients without such secretion in vitro (99.5 +/- 22.1 and 85.6 +/- 34.4 vs. 38.1 +/- 37.4 U/L; p < 0.0001, p < 0.001). Furthermore, with a histology activity score it was demonstrated that patients with in vitro IgM or IgG HCV antibodies (or both) had more severe chronic active hepatitis than did patients without in vitro hepatitis C virus antibody secretion (p < 0.01). To analyze the therapy outcome, we included in this study 18 patients who had received interferon-alpha previously. Seven of eight in vitro hepatitis C virus antibody-positive patients were nonresponders, whereas the in vitro hepatitis C virus antibody-negative patients were mostly complete therapy responders (8 of 10).(ABSTRACT TRUNCATED AT 250 WORDS)
Alanine Transaminase↗
Mixed cryoglobulinemia type II in chronic hepatitis B associated with HBe-minus HBV mutant: cellular immune reactions and response to interferon treatment.
The case of a young female patient with chronic active hepatitis B, vasculitic purpura, edema, and circulating immune complexes due to mixed cryoglobulinemia is described. Serum transaminases were elevated. Serological assays showed hepatitis B surface antigen (HBsAg), antibody to hepatitis B e antigen (anti-HBe), and antibody to hepatitis B core antigen (anti-HBc) antibodies but no antibody to hepatitis C virus (anti-HCV) or antibody to hepatitis delta virus (anti-HDV) antibodies. Using hepatitis B virus-polymerase chain reaction (HBV-PCR) and direct sequencing a precore/core (preC/C) mutant unable to synthesize HBeAg was detected in serum. HBV antigens were demonstrated in the circulating immune complexes. Following 1 month of treatment with interferon-alpha 2b3 miu three times weekly, alanine aminotransferases returned to normal levels while cryoglobulins and immune complexes disappeared from serum. In addition, 2 months after the onset of treatment serum HBV-DNA was no longer detectable by PCR. Prior to treatment the analysis of cellular immune reactions of peripheral blood mononuclear cells showed a major proliferative response to HBcAg, preS1Ag and HBxAg and a minor response to HBeAg and HBsAg. One month after conclusion of treatment a decline in T-cell reactivity against all HBV antigens was observed. During clinical response to the therapy, however, a strong proliferative response of T cells to HBcAg and HBeAg was demonstrated. In conclusion, immune complex disease may complicate chronic hepatitis B in patients expressing HBe-minus HBV mutants. Treatment with interferon-alpha was found to be effective in mixed cryoglobulinemia even in the presence of HBe-minus HBV mutants.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
[Chronic viral hepatitis and its treatment with interferon].
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Hepatitis Viruses↗
Autoreactive liver-infiltrating T cells in primary biliary cirrhosis recognize inner mitochondrial epitopes and the pyruvate dehydrogenase complex.
Primary biliary cirrhosis (PBC) is characterized by lymphoid infiltrates in the portal tracts of the liver and the occurrence of antimitochondrial autoantibodies in serum directed against components of the pyruvate dehydrogenase complex and the other alpha-keto acid dehydrogenase complexes. These enzymes are located on the inner mitochondrial membrane. The destruction of the biliary tract in PBC is thought to be mediated by autoreactive liver-infiltrating T cells exerting cytotoxic activity or releasing certain lymphokines. In this study the reactivity of liver infiltrating T cells was shown to a bovine pyruvate dehydrogenase complex (PDH), a purified E2 subunit (PDH-E2) and a crude preparation of human liver mitoplasts (HLM), i.e. mitochondria depleted of their outer membranes. Peripheral blood lymphocytes (PBL) from 11 of 15 patients (73.3%) with PBC showed a HLA class II-restricted proliferative response to the PDH complex whereas PBL from patients with chronic viral hepatitis, autoimmune hepatitis or extrahepatic cholestatic icterus (n = 20) and healthy controls (n = 5) did not. In addition 13 of 15 PBL from patients with PBC (86.6%) and three of nine PBL from patients with autoimmune hepatitis (33.3%) reacted with the crude HLM preparation whereas no reactivity was found with PBL from eight patients with chronic viral hepatitis, three patients with extrahepatic cholestasis or five healthy controls. Clonal analysis of 115 liver-infiltrating T cells derived from two diagnostic liver biopsies of patients with PBC revealed a predominance of activated CD4+CD8- T helper cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Analysis of the in vitro cytokine production by liver-infiltrating T cells of patients with autoimmune hepatitis.
The pathogenic mechanisms underlying the development of autoimmune hepatitis (AIH) are still unclear. Since AIH is associated with the presence of various autoantibodies and certain HLA subtypes, it is likely that T and B cells play a major role in this disease. In this study we have determined the functional capacities of in vivo preactivated liver-infiltrating T cells (LTC) from patients with AIH. As controls we used LTC from patients with non-autoimmune hepatitis (non-AIH). Our results show that preactivated LTC from patients with AIH predominantly (190/255 clones) reside in the CD4+ population, whereas LTC in non-AIH are dominated by the CD8+ phenotype (148/254 clones). In view of this finding we have investigated the cytokine secretion patterns of 102 randomly chosen CD4+ T cell clones from six patients with AIH. As controls we have used 58 CD4+ LTC from 11 patients with non-AIH. All clones were stimulated by lectin and irradiated accessory cells and subsequent cytokine production was evaluated. LTC from patients with AIH have a lower interferon-gamma (IFN-gamma)/IL-4 ratio compared with LTC from non-AIH. Although clones from some patients with AIH produced very high amounts of IL-4 in vitro, this was not a constant finding. These results show that in vivo preactivated LTC from patients with AIH are mostly CD4+ T cells that produce more IL-4 than IFN-gamma. In contrast, LTC from patients with non-AIH are dominated by CD8+ and CD4+ T cells that produce significantly less IL-4 than IFN-gamma. Thus, liver-infiltrating T cells from patients with AIH and non-AIH belong to different functional T cell subsets. This may have implications for the regulation of humoral and cellular immune responses in inflammatory liver disease.
Adult↗
Pneumatoceles and pneumothoraces complicating staphylococcal pneumonia: treatment by synchronous independent lung ventilation.
A 54 year old man with a staphylococcal sepsis developed staphylococcal pneumonia complicated by multiple pneumatoceles and bilateral tension pneumothoraces caused by bronchopleural fistulae. Excessive enlargement of the right sided pneumatoceles and a tension pneumothorax not improved by drainage led to mediastinal shift and compression of the right lung. Reversal of the mediastinal shift and closure of the bronchopleural fistulae was achieved by assisted independent lung ventilation.
Bronchial Fistula↗
[Infiltrating T-cells in primary biliary cirrhosis recognize mitochondrial epitopes].
The primary biliary cirrhosis (PBC) is characterized by lymphoid infiltrates in the portal tracts of the liver and occurrence of antimitochondrial autoantibodies (AMA) in serum directed against the pyruvate dehydrogenase complex or other enzyme complexes that are located on the inner mitochondrial membranes. The destruction of the biliary tracts is thought to be mediated by autoreactive liver infiltrating T-cells. In this study we demonstrate the reactivity of peripheral and liver-infiltrating T-cells against a crude preparation of human liver subcellular fractions measured by the tritium-thymidine uptake. Peripheral blood mononuclear cells (PBMC) from 13 of 15 patients with PBC and from 3 of 9 patients with chronic autoimmune hepatitis recognized human liver mitoplasts, i.e. mitochondria depleted of their outer membranes. PBMC from patients with chronic viral hepatitis B and C or with extrahepatic cholestatic icterus and PBMC from healthy controls did not recognize this antigen. Monoclonal antibodies against HLA-class II molecules blocked this proliferative response. Clonal analysis of 115 liver-infiltrating T-cells derived from two diagnostic liver biopsies of patients with PBC revealed a predominance of activated CD4+CD8- T helper cells. Six CD4- positive T-cell clones were reactive to the HLM preparation when the antigen was presented by autologous B cell lines. MAb against HLA-class II or HLA-DR inhibited the response whereas mAb against HLA-DP did not. These clones did not respond to other subcellular fractions of human liver tissue. We conclude that among liver-infiltrating T-cells in PBC autoreactive T-cells exist that recognize some epitopes on the inner mitochondrial membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
Antigen-Presenting Cells↗
Lack of surface expression for the B-cell autoepitope of cytochrome P450 IID6 evidenced by flow cytometry.
The major target antigen of LKM-1 autoantibodies in chronic active hepatitis is cytochrome P450 IID6. The role of LKM-1 autoantibodies in the pathogenesis of the disease is not clear. A crucial point is the expression of the target epitope on the hepatocyte membrane. Cultured rat hepatocytes were used in this study. Time dependent analysis of cytochrome P450 IID6 specific RNA-level revealed a constant decrease in culture. A high amount of the specific RNA-level was present after culturing the hepatocytes for 24 hours at the time of the membrane studies. To investigate membrane surface expression, we used recombinant human cytochrome P450 IID6 to affinity purify the specific autoantibody from patients sera. Indirect immunofluorescence studies and flow cytometry analysis were performed with viable, unfixed rat hepatocytes. As positive control, a monoclonal antibody against rat MHC class I antigens was used. More than 85% of viable hepatocytes showed a positive membrane staining after the incubation with the monoclonal antibody to MHC class I antigens. Affinity purified monospecific LKM-1 autoantibody, sera from control subjects and from patients with liver diseases showed a membrane staining of less than 10%. Thus, no significant expression of the B cell autoepitope of LKM-1 antigen was found on the plasma membrane of viable hepatocytes with the methods applied.
Antigens, Surface↗
Hepatitis C virus antibody secretion in vitro by peripheral blood lymphocytes.
A recombinant polypeptide corresponding to a virus-specific cDNA clone (c100-3) serves as the antigen for a hepatitis C virus (HCV) antibody assay. Previous investigations have shown an 80% prevalence of HCV antibodies in sera of patients suffering from post-transfusional chronic hepatitis non-A, non-B, but positive results were also obtained for 30 to 70% of sera from patients with chronic hepatitis B or autoimmune hepatitis. In this study we show that HCV antibodies are secreted by peripheral blood lymphocytes (PBL) in vitro. PBL from 12/35 patients with chronic non-A, non-B hepatitis and 1/6 patients with chronic active hepatitis B spontaneously secreted HCV antibodies in cell culture supernatants. The results were confirmed by neutralisation assay and ELISAs using recombinant and synthetic polypeptides derived from the c100-3 antigen and from the HCV core antigen. Two patients suffering from non-A, non-B hepatitis were negative for HCV antibodies in serum, but their PBL produced HCV c100-3 antibodies in vitro. PBL from patients suffering from autoimmune chronic hepatitis, primary biliary cirrhosis, toxic-liver injury and healthy blood donors did not produce antibodies to HCV c100 antigen irrespective of HCV antibody test results in their sera. Polyclonal B cell activation or mitogenic stimulation of T helper cells led to increased immunoglobulin synthesis by PBL in vitro, but did not lead to enhancement of specific HCV antibody production. In addition, HCV antibody production was not induced by these stimulation procedures in control lymphocytes. This spontaneous HCV antibody production in vitro suggests persistent antigenic stimulation of the B cells in vivo.
B-Lymphocytes↗
Liver-infiltrating T helper cells in autoimmune chronic active hepatitis stimulate the production of autoantibodies against the human asialoglycoprotein receptor in vitro.
Autoantibodies against the human asialoglycoprotein receptor (ASGPR) occur in the sera of patients with autoimmune liver disorders. Liver-infiltrating T cell clones that specifically recognize the ASGPR have been described in patients with autoimmune chronic active hepatitis (AI-CAH) and primary biliary cirrhosis (PBC). Recently, we have shown that peripheral blood mononuclear cells (PBMC) from patients with AI-CAH or PBC but not chronic viral hepatitis secreted anti-ASGPR antibodies in vitro. In this study we characterized the influence of liver-infiltrating T cells on the secretion of ASGPR-specific autoantibodies by autologous B cells in cell culture supernatants. T cell clones from liver biopsies of three patients with chronic autoimmune liver disorders (one with AI-CAH, two with PBC) were isolated and investigated for their proliferative response to soluble ASGPR and their helper function provided to autoantibody-secreting B lymphocytes. PBMC from these patients secreted autoantibodies spontaneously in their cell culture supernatants and showed a proliferative response to ASGPR. T cell-depleted PBMC, however, lacked spontaneous antibody secretion. Four CD4+CD8- liver-infiltrating T cell clones showed a proliferative response to ASGPR and also induced spontaneous anti-ASGPR antibody production in cell culture supernatants when added to autologous T cell depleted PBMC. Activated supernatants of these T cell clones failed to induce antibody production. None of seven CD4+CD8- and two CD4-CD8+ T cell clones non-responding to ASGPR provided this help for antibody secretion. Anti-ASGPR secretion in vitro could not be inhibited by the addition of MoAbs raised against monomorphic determinants on HLA class II molecules. The addition of purified ASGPR or polyclonal-activating pokeweed mitogen showed no influence on the production of autoantibodies in these cultures. These data show that B lymphocytes require T cell help for the production of ASGPR-specific antibodies. This help can be provided by ASGPR-responsive T helper cells via cellular interactions.
Adult↗
Human asialoglycoprotein receptor as an autoantigen in chronic hepatitis.
ASGPR may play a role in the pathogenesis of autoimmune chronic liver diseases. Several lines of evidence support this hypothesis. Antibodies to rabbit ASGPR could be found in various inflammatory liver diseases. In contrast, ASGPR preparations derived from human liver (h-ASGPR) were recognized predominantly by sera from patients with ai-CAH. Moreover, anti-h-ASGPR showed a close correlation to the inflammatory activity of ai-CAH both in terms of prevalence (88% in histologically proven active diseases), immunoglobulin class (IgM antibodies restricted to active inflammation) and behavior during treatment. Anti-h-ASGPR secretion could also be found in vitro, when PBL of patients were stimulated in cell culture. Anti-h-ASGPR antibodies did not correlate with a subgroup of ai-CAH; they also occurred in nearly 15% of patients with PBC. Other inflammatory liver diseases, as well as nonhepatic autoimmune disorders, seldom exhibited anti-h-ASGPR (less than 5%). Additionally, PBL and T-cell clones obtained from liver biopsies in patients with ai-CAH and PBC responded to h-ASGPR. Liver-infiltrating T cells were predominantly of CD4 phenotype and HLA class II restricted. Thus, the human ASGPR has been shown to represent a common target for humoral and cellular autoimmune response in chronic hepatitis probably contributing to disease induction or perpetuation.
Animals↗