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Biomedical subjects

U Spengler

Publications and source records attributed to U Spengler.

At least 127 records · Page 7Linked to original sources
PubMed1997

The IL-1 system in HIV infection: peripheral concentrations of IL-1beta, IL-1 receptor antagonist and soluble IL-1 receptor type II.

The proinflammatory cytokine IL-1beta is thought to be involved in ongoing HIV disease. Furthermore, its naturally occurring inhibitors soluble IL-1 receptor type II (sIL-1RII) and IL-1 receptor antagonist (IL-1Ra) may play a pivotal role in regulating its biological action. To investigate the involvement of the IL-1 system we determined serum levels of IL-1beta, IL-1Ra and sIL-1RII in 90 HIV- patients. The obtained values were compared with markers of disease progression such as CD4+ count, 5'-neopterin. Beta2-microglobulin and soluble tumour necrosis factor receptors (sTNF-R) p55 and p75 and then compared with C-reactive protein (CRP), granulocyte count, IL-6 and TNF-alpha. While IL-1Ra concentrations increased significantly with progressive CDC disease stages, sIL-1RII and IL-1beta were not altered in our cohort. IL-1Ra showed statistical relation to decreasing CD4+ lymphocytes and increasing 5'-neopterin, beta2-microglobulin, sTNF-R p55, sTNF-R p75. Furthermore, IL-1Ra correlated positively with serum IL-6, TNF-alpha, CRP and granulocytes. In contrast, sIL-1RII and IL-1beta tended to show an inverse correlation or showed no significant relationship to all these parameters. IL-1beta was measurable only in a limited number of samples. IL-1Ra showed a clear relationship to acute inflammatory events as well as to the different disease stages. Our data suggest a dissociation between IL-1Ra and sIL-1RII serum levels which may indicate that the two IL-1 binding proteins have different pathophysiological roles in HIV infection.

Adult↗
PubMed1997

Plasmid DNA expressing a secreted or a nonsecreted form of hepatitis C virus nucleocapsid: comparative studies of antibody and T-helper responses following genetic immunization.

In a murine model, we have compared humoral and T-helper (Th) responses induced following genetic immunization with two hepatitis C virus (HCV) plasmid-derived immunogens: a plasmid expressing the full-length nucleocapsid (CAP) as a nonsecreted antigen (pCMVC2) and a plasmid expressing the amino-terminal part of CAP as a secreted antigen (pS2S.C2N). In BALB/c mice, intramuscular injection of either plasmid induced IgG2a antibodies associated with a Th1-like profile characterized by the in vitro splenic production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma). The pS2S.C2N plasmid induced antibody titers three- to five-fold higher than those obtained with the pCMVC2 plasmid (maximal titers 1:1,500 versus 1:500). In control experiments, immunization using purified CAP antigen induced a predominant, but not exclusive, Th2-like profile as determined by the splenic production of IL-4 and IL-10. Six putative Th determinants were identified using a panoply of overlapping synthetic peptides in in vitro stimulation assays: amino acids 20-44, 39-63, 79-113, 89-113, 118-142, and 138-152. For all CAP immunogens, MHC haplotype of immunized mice was found to influence seroconversion rates but not the type of cytokines produced in vitro. H-2d mice were faster responders and displayed recall T-cell activation by a larger number of peptides than H-2b mice, whereas H-2s mice were overall very poor responders. Splenic stimulation by at least one determinant, amino acids 79-103, appeared to be highly specific of the H-2b background and of DNA immunization only. These data indicate that DNA immunogens expressing different forms of HCV-CAP are not associated with different Th profiles but rather different seroconversion rates and antibody titers and that collaboration of distinct T-help epitopes can be restricted by the MHC background.

Animals↗
PubMed1997

Semiquantitative analysis of intrahepatic cytokine mRNAs in chronic hepatitis C.

In order to characterize intrahepatic cytokine production, the mRNA levels of interleukin (IL)-2, -4, and -10 and interferon (IFN)-gamma were semiquantitatively determined by reverse-transcription competitive polymerase chain reaction in liver specimens from patients with chronic hepatitis C (n = 23), chronic hepatitis B (n = 9), or primary biliary cirrhosis (n = 12) and normal liver (control) specimens (n = 12). IL-4 mRNA was undetectable. Similar IL-10 mRNA levels were detected in all samples studied, including the controls. Mean IFN-gamma and IL-2 mRNA levels were elevated in chronic inflammatory liver disease. IL-2 mRNA levels were similar in all 3 patient groups, but intrahepatic IFN-gamma mRNA levels were significantly higher in chronic hepatitis C than in chronic hepatitis B or primary biliary cirrhosis patients. This predominance of IFN-gamma may indicate a lower susceptibility of hepatitis C virus to the antiviral effects of this cytokine. The presence of IL-10 in normal liver may impair the induction of antiviral immune responses.

Actins↗
PubMed1997

Relationship between cytochrome P-450 induction by rifampicin, hepatic volume and portal blood flow in man.

OBJECTIVE: Induction of hepatic cytochrome P-450-dependent oxidative metabolism is related to an almost identical increase (30%) in both the liver weight and portal blood flow in animals. In humans by contrast, an increased liver blood flow (44%) but no significant increase in liver volume has been reported. DESIGN: Therefore, we studied prospectively the relationship between P-450 induction by rifampicin, hepatic volume and portal blood flow in 10 healthy volunteers. METHODS: After a pre-treatment phase (day 1 to 7) the 10 volunteers received 600 mg/day of rifampicin from day 7 to 12. The urinary 6-beta-hydroxycortisol output as a measure of oxidative metabolism (CYP3A4) and portal blood flow (pulsed Doppler ultrasound) were determined on days 1, 7, 11 and 13. Hepatic magnetic resonance volumetry was performed on days 1 and 13. RESULTS: Urinary 6-beta-hydroxycortisol output increased in all volunteers (P = 0.0051) from a median of 2.15 micrograms/day/kg (1.8-3.3 micrograms/day/kg) on day 1 to 9.9 micrograms/day/kg (5.7-14 micrograms/day/kg) on day 13. In 9 of 10 volunteers induction by rifampicin was related to an increase (P = 0.0218) in liver volume from a median of 1570 cm3 (1390-1830 cm3) to a median of 1690 cm3 (1420-1860 cm3). The portal flow as assessed by colour Doppler ultrasound did not change significantly between day 1 (median 22 cm/s (15-35 cm/s)) and day 13 (median 19 cm/s (16-39 cm/s)). CONCLUSION: A fourfold increase of urinary 6-beta-hydroxycortisol output after induction of cytochrome P-450 by rifampicin is associated with a significant but less than 10% increase in human liver volume. No increase of portal perfusion as assessed by Doppler ultrasound could be detected in this study.

Adult↗
PubMed1997

Hepatitis C virus-associated mixed cryoglobulinaemia.

Symptomatic mixed cryoglobulinaemia may dominate the course of hepatitis C virus infection. While conventional treatment of mixed cryoglobulinaemia relied on immunosuppression, the discovery of the close association to HCV infection has prompted treatment studies with interferon-alpha. Although symptomatic improvement is achieved in most patients during therapy, the rate of sustained response is low.

Cryoglobulinemia↗
PubMed1996

[Occurrence and significance of autoantibodies in the course of interferon therapy of chronic hepatitis C].

BASIC PROBLEM AND OBJECTIVE: Autoimmunity may occur in chronic hepatitis C (CHC) as a primary event or may be induced by interferon-alpha (IFN-alpha). The existence of autoantibodies (AAB) is considered to be a contraindication to interferon treatment. It was the aim of this study to determine the extent to which signs of autoimmune disease occur in the treatment of CHC with interferon, even in patients with existing antibodies. PATIENTS AND METHODS: In 1994 a pre-defined AAB spectrum and thyroid function parameters were determined every other month in 41 patients with CHC (16 women, 25 men; median age 42 years) before and after they had been treated with IFN-alpha, even when AABs were already present. RESULTS: AABs were demonstrated in 17 patients (41%) before and in 26 (63%) during interferon treatment (P = 0.001). In 13 patients new AABs were demonstrated, while previously present AABs were no longer found in four patients. AABs against thyroglobulin (TGA) increased significantly, during interferon treatment (P = 0.001). All except thyroid AABs were demonstrable only at times and in low titres. None of the patients had an auto-immune disease before treatment. But autoimmune thyroiditis developed in four of 19 patients with thyroid AABs. These patients also had constant TGAs in high titres, and antibodies against microsomes were additionally demonstrated in two. No other autoimmune disease occurred during or after interferon treatment. CONCLUSION: Interferon frequently induces the formation of AABs. The demonstration of AABs before or during interferon treatment is no contraindication to it, with the exception of preexisting thyroid antibodies, which indicate a high risk of autoimmune thyroiditis.

Adult↗
PubMed1996

A comparative study of different enzyme immunosorbent assays for human tumor necrosis factor-alpha.

Enzyme immunosorbent assays (ELISA) for human tumor necrosis factor-alpha (TNF-alpha) are available from many companies. Although this cytokine is meanwhile well established in scientific work its detection in human blood still leads often to conflicting results. We studied the analytical performance of three different commercial ELISA (Amersham, Immunotech and Medgenix Diagnostics) in plasma samples of 30 human immunodeficiency virus (HIV) infected individuals. All kits showed significantly different mean concentrations of TNF-alpha in the study population (p < 0.05). Kit A: 30.9 pg/ml +/- 46.6 vs. kit B: 46.9 pg/ml +/- 24.8 vs kit C: 11.8 pg/ml +/- 11.6. Results of assays A and B (r = 0.34) as well as A and C (r = 0.31) were not significantly correlated. A good statistical relation between values was only found for assay B and assay C (r = 0.80. p < 0.001). Three plasma samples were spiked with TNF-alpha standard of the corresponding kit to a final concentration of 200 pg/ml. The detection results of these samples were compared with the variation conceded by the manufacturer. Assay A detected two samples above the corresponding coefficient of intra-assay variation (recovery: 81.8% and 89.2%). All three values obtained with assay B were markedly out of its variation range (recovery: 88.7%, 84.6% and 89.0%) while assay C showed again two results above the intra-assay variation (recovery: 92.1% and 89.6%). In our observations we found relevant differences between commercial ELISA kits of different manufacturers, which made interpretation of TNF-alpha in human plasma samples difficult. Additionally, it should be taken into consideration that plasma specimen may contain cytokine-binding proteins or autoantibodies which are capable of blocking epitopes of TNF-alpha. This may lead to the loss of the necessary immunoreactivity which prevents detection antibodies from recognizing these molecules.

Enzyme-Linked Immunosorbent Assay↗
PubMed1996

Hepatic levels of bile acids in end-stage chronic cholestatic liver disease.

In chronic cholestatic liver disease hydrophobic and potentially cytotoxic bile acids are assumed to accumulate in the liver. To test this hypothesis we investigated bile acid levels and pattern in livers and serum of patients with, (A) end-stage chronic cholestatic liver disease, and with (B) end-stage cirrhosis of alcoholic/chronic hepatitic origin who underwent liver transplantation. Bile acids were also analyzed in (C) normal liver tissue. Levels of bile acids were 215 +/- 39.1 nmol/g liver (wet weight) in chronic cholestasis and 120 +/- 32.7 and 56.1 +/- 24.2 nmol/g liver in group B and group C (P < 0.01 and P < 0.005), respectively. Cholic acid was the prevailing bile acid in chronic cholestasis (51%) and was elevated eight-fold as compared to group C (P < 0.005). Chenodeoxycholic acid contributed 41% to total bile acids and was elevated four-fold (P < 0.005). Deoxycholic acid contributed only 1.5% to bile acids in chronic cholestasis as compared to 27% in group C (P < 0.01) and was absent in group B. Levels of lithocholic acid tended to be increased in chronic cholestasis as compared to group C and its sulfation was impaired (P < 0.05). The pattern of serum bile acids in chronic cholestasis agreed well with the bile acid pattern in the explanted livers. We conclude that hepatic accumulation of hydrophobic chenodeoxycholic acid and impaired sulfation of lithocholic acid might contribute to tissue degeneration in chronic cholestatic liver disease due to the detergent effects of these bile acids.

Aged↗
PubMed1996

T- and B-cell responses to different hepatitis C virus antigens in patients with chronic hepatitis C infection and in healthy anti-hepatitis C virus--positive blood donors without viremia.

As the host's immune response may determine the course of hepatitis C virus (HCV) infection, we studied the humoral and cellular immune responses to HCV-related antigens in subjects with different outcomes of HCV infection. Lymphoproliferative responses and circulating antibodies to a panel of HCV core- and E1-related 25-mer peptides were examined in 10 healthy anti-HCV-seropositive blood donors (group A) and in 29 patients with chronic hepatitis C (group B). In addition, cellular recognition of recombinant HCV proteins (core, NS3, NS4A, NS5A, NS5B) were investigated. In group A, stronger T-cell responses were detected against both HCV proteins (core, P = .03; NS4, P = .005; NS5B, P = .03) and peptides. Proliferation was induced by the same peptides in each group, defining at least five distinctive epitopes within core (amino acids [aa] of 20-44, aa 39-63, aa 79-103, aa 118-152 and aa 148-172) and three regions within E1(aa 198-252, aa 308-372, and aa 368-392). Subjects with strong T-cell responses had low or no detectable levels of peptide-specific antibodies, and vice versa. In particular, T-cell responses were more common in group A; B-cell responses were more common in group B. From our data, we conclude that a benign course of HCV infection may be the consequence of the effective activation of T-helper lymphocytes.

Adolescent↗
PubMed1996

Serum levels and in situ expression of TNF-alpha and TNF-alpha binding proteins in inflammatory liver diseases.

Cells respond to tumour necrosis factor-alpha (TNF-alpha) via binding to 75-kDa (type A) and 55-kDa (type B) receptors which have different intracellular signalling pathways and can also circulate as soluble molecules. Both receptors are co-expressed in many tissues, but their relative contributions to cellular TNF responses is for most situations unknown. In patients with viral and non-viral inflammatory liver diseases serum TNF-alpha was determined by an immunoenzymetric assay and soluble type A and B TNF receptors (TNF-alpha r) by enzyme-linked immunological and biological assays (ELIBA). In addition, cellular expression of TNF and its binding proteins were studied in liver biopsies by an indirect immunoperoxidase technique. Secretion of TNF-alpha and upregulation of TNF-alpha r-A were particularly prominent in viral hepatitis. Strong TNF-alpha in-situ production by mononuclear cells could be demonstrated in liver biopsies from patients with acute viral hepatitis. However, TNF-alpha r-A was detected only on hepatocytes. Serum TNF-alpha r-A was elevated two-fold in relative abundance over TNF-alpha r-B and was correlated to serum TNF-alpha (r = 0.6464, P < 0.0001). Soluble TNF-alpha r levels normalized, when the viral hepatitis was cleared, and successful therapy of hepatitis B was associated with a temporary rise of TNF-alpha r-A during the initial flare of aminotransferase. Patients with alcoholic hepatitis had also evidence of TNF-alpha activation but clearly differed from patients with viral induced liver diseases: Soluble TNF-alpha r-A and TNF-alpha r-B were highly elevated in equal proportions. In situ analysis in liver biopsies revealed a distinctive pattern of TNF-alpha r expression with strong cytoplasmic staining for both TNF-alpha r-A and B on scattered hepatocytes in addition to infiltrating mononuclear cells. The data propose that TNF release during antiviral immune responses is predominantly associated with TNF-alpha r-A upregulation and shedding, whereas upregulation and shedding of TNF-alpha r-B is more prominent in alcoholic hepatitis. As cytotoxicity and apoptosis by TNF are mediated mainly via TNF-alpha r-B, our results are consistent with more severe TNF-alpha induced liver damage in alcoholic hepatitis as compared to viral hepatitis.

Antigens, CD↗
PubMed1996

Splenic abscesses and abdominal tuberculosis in patients with AIDS.

Tuberculous splenic abscesses do virtually not occur in immunocompetent patients. Tuberculous abscesses have been reported only from areas, where the prevalence of both HIV infection and tuberculosis is very high such as Central Africa. In our institution two of seven patients with AIDS and disseminated tuberculosis who were treated during the year 1994 developed tuberculous splenic abscesses. Both patients were resident in Central Europe and had fever and weight loss prior to admission. Multiple hypoechoic lesions up to 1.5 cm in diameter developed in the spleen of both patients on day 11 and 16 after admission, respectively. Initially no symptoms related to the splenic involvement and no leucocytosis were seen in both patients. One patient developed leucocytosis and left sided flank pain caused by a subtotal splenic abscess because the diagnosis and therapy of tuberculosis was delayed. Both patients responded promptly to triple drug antituberculous therapy without surgical intervention. We conclude that also in European patients multiple hypoechoic/hypodense lesions in the spleen of HIV positive patients are highly suggestive of disseminated tuberculosis. Follow-up by ultrasound may help to establish the correct diagnosis and may further prevent unnecessary complications in these patients.

AIDS-Related Opportunistic Infections↗
PubMed1996

Immune responses in hepatitis C virus infection.

Infection with the hepatitis C virus (HCV) commonly causes persistent disease, which may lead to cirrhosis and hepatocellular carcinoma. The pathogenesis of HCV infection is not well understood. It is most likely that both viral and host factors contribute to HCV persistence. This review focuses on the host's immune response to HCV in an attempt to present the current knowledge and concepts of the interactions between the virus and the host during HCV infection. Expansion of B lymphocytes and antibody production to virtually any HCV protein can be detected in most infected patients. However, observations in HCV-infected humans as well as experimental infections in chimpanzees suggest that natural HCV infection does not induce protective immunity, and reinfection can readily be demonstrated after inoculation with homologous or independent strains in HCV-seroconverted animals. Nevertheless, the immune system may gain partial control over HCV even in patients with chronic infection, as HCV infection in severely immunocompromised patients runs a particular cholestatic course which may rapidly lead to death from liver failure. Cytotoxic CD8+ T lymphocyte responses to HCV proteins have been characterized in peripheral blood and liver tissue and were found to be remarkably polyclonal and multispecific. Epitopes were identified on all of the putative HCV proteins, although only few major histocompatibility complex molecules were considered restriction elements. Immunoregulation may be particularly important in HCV infection. The HCV core and NS4 proteins appear to be most immunogenic for peripheral blood lymphocytes, and NS4 specific CD4+ lymphocytes are preferentially compartmentalized to the liver. However, there is an inverse relationship between CD4+ lymphocyte responses and antibody levels in infected patients. Furthermore, a strong cellular response to the HCV core protein apparently favors a benign course of infection. This unusual T-B cell relationship may be the consequence of an altered cytokine release during HCV infection. Alternatively, this virus may have found devices that can disturb immunoregulation in infected patients. A better understanding of these immunological mechanisms induced by HCV infection should make it possible to develop more effective strategies for the prevention and treatment of this insidious disease.

CD4-Positive T-Lymphocytes↗
PubMed1996

Immunosuppression may lead to progression of hepatitis C virus-associated liver disease in hemophiliacs coinfected with HIV.

OBJECTIVE: The aim of this study was to examine the interaction between HIV and hepatitis C virus (HCV) in hemophiliacs coinfected with the viruses and to investigate the possible relationship between immunosuppression and liver failure. METHODS: To identify risk factors for impending liver failure in hemophiliacs coinfected with HIV and HCV, we analyzed clinical and laboratory parameters, including CD4 count, aminotransferases (ALT, AST), cholinesterase, alkaline phosphatase, bilirubin, and gamma-glutamyltransferase, during 3 yr of follow-up (1990-1993) in four groups of patients: hemophiliacs with progressive immunodeficiency who were coinfected with HCV and HIV (group A, n = 49); hemophiliacs with stable immune function who were seropositive for HIV and HCV (group B, n = 95); hemophiliacs who were infected with HCV but not HIV (group C, n = 72); and homosexuals with progressive immunodeficiency who were infected with HIV but not HCV (group D, n = 24). RESULTS: Univariate analysis of data for group A showed a significant rise in gamma-glutamyltransferase and alkaline phosphatase (p < 0.01) that was not seen in groups B, C, and D. In a multivariate Cox regression analysis, age (odds ratio, 1.054 per yr; 95% confidence interval, 1.014-1.096 per yr), decline in CD4 count (odds ratio, 1.063 per cell/microl; 95% confidence interval, 1.037-1.091 per cell/microl), and alkaline phosphatase level (odds ratio, 1.012 per U/L; 95% confidence interval, 1.002-1.021 per U/L) emerged as independent determinants of death. CONCLUSIONS: Our data suggest that progressive immune dysfunction in hemophiliacs coinfected with HIV and HCV may influence progression of liver failure. In these patients cholestasis is an additional prognostic marker for survival that may reflect both exhausted immunity and impaired liver function.

Acquired Immunodeficiency Syndrome↗