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S Kanzler

Publications and source records attributed to S Kanzler.

31 records · Page 2Linked to original sources
PubMed2000

Apoptosis and the liver.

Regulation of the homeostatic balance between cell proliferation and programmed cell death, apoptosis, is essential for development and maintenance of multicellular organisms. Apoptosis is a genetically and evolutionarily highly conserved process. Analysis of the molecular mechanisms of apoptosis has led to a better understanding of many human diseases. Notably in cancer, but also in infectious or autoimmune disease, a deficiency in apoptosis is one of the key events in pathophysiology. On the other hand, overefficient apoptosis, as observed in fulminant liver failure, may be equally harmful for the organism indicating that a tight regulation of the apoptotic machinery is essential for survival. The execution of apoptosis may be initiated by many different signals, either from within or outside the cell involving ligand-receptor interactions, as has been shown for Fas/Fas-ligand, TNF-alpha/TNF-receptor or TGF-beta/TGF-receptor, or potentially by more unspecific signals such as ceramide or DNA damage. During the modulation phase of apoptosis many different genes such as p53, c-myc or Bcl-2/Bax have been shown to able to shift the balance either to cell survival or cell death.

Apoptosis↗
PubMed1999

Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens.

We generated transgenic mice for STAT-4, a regulatory protein specifically associated with IL-12 signaling, under the control of a CMV promoter. These mice expressed strikingly increased nuclear STAT-4 levels in lamina propria CD4+ T lymphocytes upon systemic administration of dinitrophenyl-keyhole limpet hemocyanin and developed chronic transmural colitis characterized by infiltrates of mainly CD4+ T lymphocytes. The latter cells produced predominantly TNF and IFN-gamma but not IL-4 upon activation with alphaCD3/CD28 or autologous bacterial Ags, consistent with a Th1-type cell response. Furthermore, chronic colitis in STAT-4 transgenic mice could be adoptively transferred to SCID mice by colonic and splenic CD4+ T cells that were activated with Ags from autologous bacterial flora. These data establish a critical molecular signaling pathway involving STAT-4 for the pathogenesis of chronic intestinal inflammation, and targeting of this pathway may be relevant for the treatment of colitis in humans.

Adoptive Transfer↗
PubMed1999

Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence for it being a hepatitic form of PBC in genetically susceptible individuals.

Some patients with autoimmune liver disease present with a clinical and/or histological picture showing characteristic findings of both autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Various names, mostly overlap syndrome, have been used to describe these cases, which have thus far not been more closely characterized. The aim of this study was the comparison of 20 patients with overlapping features to representative patients considered suffering from typical AIH or typical PBC (20 patients in each group). We found these patients to indeed show a very mixed picture of both conditions biochemically, serologically, and histologically. However, closer analysis suggested that all of these patients were primarily suffering from PBC as all of them had at least either bile duct destruction on histology or anti-M2 positive antimitochondrial antibodies (AMA). We suggest that these PBC patients because of their genetic susceptibility, evidenced by the AIH-characteristic histocompatibility leukocyte antigen (HLA) type B8, DR3, or DR4, developed a more hepatitic picture. Response to immunosuppressive therapy was excellent. We propose that the name "overlap syndrome" be abandoned for "PBC, hepatitic form." These observations not only have pathophysiological implications, but also suggest that therapy of PBC should be guided by the degree of biochemical and histological hepatic involvement.

Adolescent↗
PubMed1999

Clinical significance of autoantibodies to soluble liver antigen in autoimmune hepatitis.

BACKGROUND/AIMS: Classification of autoimmune hepatitis (AIH) into different subgroups according to autoantibody status has been proposed: type I (ANA/SMA), type II (LKM-1) and type III (anti-SLA). However, whether type III AIH forms a clinically distinct disease entity remains controversial. The aim of this study was to evaluate the subclassification of AIH into ANA/SMA and anti-SLA positive patients with regard to clinical, biochemical and histologic differences. METHODS: Ninety-seven consecutive patients with a well-documented long-term course of AIH with ANA/SMA and/or anti-SLA autoantibodies were studied. Clinical, biochemical and histological features of patients with ANA/SMA and/or anti-SLA autoantibodies were compared in a secondary analysis of data acquired prospectively. RESULTS: Anti-SLA autoantibodies were found in 21.6% of patients. Anti-SLA-positive patients tended to have lower transaminases (mean: 153 vs. 247 IU/l), gamma-globulins (25 vs. 31%) and bilirubin (1.8 vs. 3.3 mg/dl) in comparison to ANA/SMA positive patients, but there was a large overlap. HLA-type A1 B8 was more frequent in anti-SLA positive patients, while there was no difference in HLA DR3 and DR4 allotype. Response to immunosuppressive therapy was excellent, but relapse occurred frequently. Diagnosis of anti-SLA positive AIH was often delayed (mean: 68 months from first elevation of transaminases) since testing for anti-SLA autoantibodies is currently not generally available. CONCLUSIONS: ANA/SMA and anti-SLA positive patients share most clinical, biochemical, histologic and prognostic features. Distinction between type I and type III AIH is therefore clinically not helpful. However, testing for anti-SLA autoantibodies helps in the diagnosis of AIH in many patients who may otherwise be misdiagnosed.

Adult↗
PubMed1999

TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis.

Transforming growth factor-beta1 (TGF-beta1) is a powerful stimulus for collagen formation in vitro. To determine the in vivo effects of TGF-beta1 on liver fibrogenesis, we generated transgenic mice overexpressing a fusion gene [C-reactive protein (CRP)/TGF-beta1] consisting of the cDNA coding for an activated form of TGF-beta1 under the control of the regulatory elements of the inducible human CRP gene promoter. Two transgenic lines were generated with liver-specific overexpression of mature TGF-beta1. After induction of the acute phase response (15 h) with lipopolysaccharide (100 microgram ip), plasma TGF-beta1 levels reached >600 ng/ml in transgenic animals, which is >100 times above normal plasma levels. Basal plasma levels of uninduced transgenic animals were about two to five times above normal. As a consequence of hepatic TGF-beta1 expression, we could demonstrate marked transient upregulation of procollagen I and procollagen III mRNA in the liver 15 h after the peak of TGF-beta1 expression. Liver histology after repeated induction of transgene expression showed an activation of hepatic stellate cells in both transgenic lines. The fibrotic process was characterized by perisinusoidal deposition of collagen in a linear pattern. This transgenic mouse model gives in vivo evidence for the important role of TGF-beta1 in stellate cell activation and liver fibrogenesis. Due to the ability to control the level of TGF-beta1 expression, this model allows the study of the regulation and kinetics of collagen synthesis and fibrolysis as well as the degree of reversibility of liver fibrosis. The CRP/TGF-beta1 transgenic mouse model may finally serve as a model for the testing of antifibrogenic agents.

Animals↗
PubMed1998

Transforming growth factor-beta1 in autoimmune hepatitis: correlation of liver tissue expression and serum levels with disease activity.

BACKGROUND/AIMS: Transforming growth factor-beta1 (TGF-beta1) is considered the most important mediator of hepatic fibrogenesis. At the same time, TGF-beta1 is an immunosuppressive cytokine. Development of fibrosis, often rapid, is a characteristic of autoimmune hepatitis, as is spontaneous systemic immunosuppression. The aim of our study was therefore to define the role of TGF-beta1 in autoimmune hepatitis. METHODS/RESULTS: Using the MV 1Lu bioassay, we found markedly elevated serum levels of TGF-beta1 (median 109 ng/ml) in active autoimmune hepatitis, which normalised when patients reached biochemical remission following immunosuppressive therapy (median 34 ng/ml; p=0.0001 compared to active disease). With a newly established ELISPOT-assay for TGF-beta1-producing cells, we could exclude an increase in TGF-beta1-producing peripheral blood cells as a source of the elevated TGF-beta1. However, by in situ hybridisation and immunohistochemistry, we found strong TGF-beta1 expression in the inflamed liver. In addition to non-parenchymal and infiltrating cells, many hepatocytes showed strong staining for TGF-beta1. TGF-beta1 expression in the liver normalised in remission, yet was still somewhat increased in patients with biochemical remission but remaining histological disease activity. CONCLUSIONS: These results suggest that TGF-beta1 is an important mediator in active autoimmune hepatitis. They support the theory that immunosuppressive therapy needs to be guided by histology, as prevention of the development of cirrhosis presumably requires near complete suppression of TGF-beta1 in the liver; this is only found when there is no longer any histological evidence of inflammation.

Adolescent↗
PubMed1997

Autoimmune findings resembling connective tissue disease in a patient with Castleman's disease.

Multicentric angiofollicular lymphnode hyperplasia (multicentric Castleman's disease) may be associated with acute phase reaction and several autoimmune features. Since lymphadenopathy is a common feature in connective tissue disease, a clear distinction between the different disease entities may be difficult. We describe a 26-year-old male patient with predominant cervical lymphadenopathy, hepatosplenomegaly and polyserositis, diagnosed as collagen disease. He showed several autoimmune features including autoimmune haemolytic anaemia, cryoglobulinaemia, positive antinuclear and anti smooth muscle antibodies, serum immune complexes and a sensorimotor polyneuropathy. Under immunosuppressive therapy with prednisolone and azathioprine, only partial remission was achieved. Repeated lymph node biopsy together with the clinical features led to the diagnosis of multicentric Castleman's disease in this patient nine years later. Interleukin-6 (IL-6) seems to play an important role in the pathogenesis of clinical and serum biochemical features in patients with Castleman's disease.

Adult↗
PubMed1997

Cyclophosphamide as alternative immunosuppressive therapy for autoimmune hepatitis--report of three cases.

Autoimmune hepatitis is a chronic inflammatory disorder of the liver with a fluctuating course, which often requires long-term immunosuppressive therapy in order to prevent fibrosis to the liver. The mainstay of immunosuppressive therapy is the use of corticosteroids, usually in conjunction with azathioprine. However, in a subgroup of patients with severe side effects or intolerance of standard therapy there is a need for alternative immunosuppressive agents. We describe the successful long-term treatment of three patients with severe autoimmune hepatitis with an immunosuppressive regimen consisting of cyclophosphamide and corticosteroids. In the reported patients we were able to induce remission with cyclophosphamide in a dose of 1-1.5 mg/kg bodyweight in combination with a tapering dose of corticosteroids beginning with 1 mg/kg bodyweight. After induction we were able to maintain histology proven remission with low doses of corticosteroids (2.5-10 mg/day) together with 50 mg of cyclophosphamide every other day. With this dose of cyclophosphamide we have neither observed relapse of autoimmune hepatitis nor severe side effects in a cumulative observation period of more than twelve years in the three patients. As a consequence of our favourable experience with cyclophosphamide in the reported cases, we propose cyclophosphamide as an alternative to azathioprine in cases of autoimmune hepatitis with severe side effects of intolerance of standard therapy.

Adult↗
PubMed1996

Complete reversal of FK 506 induced diabetes in a liver transplant recipient by change of immunosuppression to cyclosporine A.

We report the case of a 41-year old patient who underwent orthotopic liver transplantation because of decompensated liver cirrhosis due to chronic HCV-infection. Severe acute allograft rejection was insufficiently controlled by cyclosporine A, steroids and a 6-day regimen of OKT 3 monoclonal antibody therapy. As a consequence immunosuppressive therapy was switched to FK 506 in a dose of 3 mg bid. The FK 506 concentration in whole blood consistently ranged between 5.1 and 7.8 ng/ml. Seven weeks after the onset of FK 506 therapy the patient developed severe diabetes mellitus with fasting blood glucose levels up to 640 mmol/l. The C-peptide was elevated reflecting a higher than normal insulin secretion. Intravenous insulin therapy with application of up to 85 units regular insulin per day was initiated. Because of the severe diabetes immunosuppression was changed back to cyclosporine A. After six weeks the patient did no longer require insulin and showed an entirely normal glucose tolerance test, C-peptide and Hb A1-level. This case shows that the diabetogenic side effect of FK 506 is more pronounced than that of cyclosporine A. We propose to change immunosuppressive therapy to cyclosporine A in cases of FK 506 induced severe diabetes mellitus, since long-term prognosis of many transplant recipients may depend on side effects of the immunosuppressive agents.

Adult↗
PubMed1995

[Therapy refractory atypical polyarthritis and cryoglobulinemia in a patient with colon carcinoma and palliative intestinal bypass. Differential diagnosis: carcinoma-polyarthritis or bypass arthritis].

The case of a 63 year old woman with mesenteric recurrence of a colonic carcinoma and infiltration of the duodenum is reported. To bypass duodenal stenosis a duodenojejunostomy was performed. Three months later the patient developed severe atypical polyarthritis which led to hospitalization. The arthritis affected large and small joints in an asymmetrical pattern. Fever and Raynaud's phenomenon of both hands accompanied the arthritis. Elevated sedimentation rate, acute phase proteins, cryoglobulinemia and immune complexes were remarkable laboratory findings. Rheumatoid factor was absent. In the subsequent course the polyarthritis was refractory to steroids and nonsteroidal anti-inflammatory drugs. Only treatment with broad-spectrum antibiotics ameliorated the arthritis. Postenteric reactive arthritis, septic arthritis and metastatic arthritis could be excluded. Although the patient had a family history of rheumatoid arthritis and a HLA-type DR4 the diagnosis of rheumatoid arthritis was not very likely since distal interphalangeal joints were affected, rheumatoid factor was absent and antibiotic therapy was successful. The case serves to discuss carcinoma-polyarthritis and bypass-arthritis as the main differential diagnosis.

Adenocarcinoma↗