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Biomedical subjects

H Wedemeyer

Publications and source records attributed to H Wedemeyer.

At least 37 records · Page 2Linked to original sources
PubMed2001

Treatment of acute hepatitis C with interferon alfa-2b.

BACKGROUND: In people who are infected with the hepatitis C virus (HCV) chronic infection often develops and is difficult to eradicate. We sought to determine whether treatment during the acute phase could prevent the development of chronic infection. METHODS: Between 1998 and 2001, we identified 44 patients throughout Germany who had acute hepatitis C. Patients received 5 million U of interferon alfa-2b subcutaneously daily for 4 weeks and then three times per week for another 20 weeks. Serum HCV RNA levels were measured before and during therapy and 24 weeks after the end of therapy. RESULTS: The mean age of the 44 patients was 36 years; 25 were women. Nine became infected with HCV through intravenous drug use, 14 through a needle-stick injury, 7 through medical procedures, and 10 through sexual contact; the mode of infection could not be determined in 4. The average time from infection to the first signs or symptoms of hepatitis was 54 days, and the average time from infection until the start of therapy was 89 days. At the end of both therapy and follow-up, 43 patients (98 percent) had undetectable levels of HCV RNA in serum and normal serum alanine aminotransferase levels. Levels of HCV RNA became undetectable after an average of 3.2 weeks of treatment. Therapy was well tolerated in all but one patient, who stopped therapy after 12 weeks because of side effects. CONCLUSIONS: Treatment of acute hepatitis C with interferon alfa-2b prevents chronic infection.

Acute Disease↗
PubMed2001

Oral immunization with HCV-NS3-transformed Salmonella: induction of HCV-specific CTL in a transgenic mouse model.

BACKGROUND & AIMS: The ability to induce cytotoxic T cells is considered an important feature of a candidate hepatitis C virus (HCV) vaccine. We used an oral immunization strategy with attenuated HCV-NS3-transformed Salmonella typhimurium to deliver DNA directly to the gut-associated lymphoid tissue. METHODS: HLA-A2.1 transgenic mice were immunized once with transformed attenuated Salmonella. HCV-specific CD8+ T cells were analyzed in vitro as well as in vivo by challenge of mice with recombinant HCV-NS3 vaccinia virus. RESULTS: Salmonella (10(8) colony-forming units; 20 microg plasmid DNA) induced cytotoxic and IFN-gamma-producing CD8+ T cells specific for the immunodominant epitope NS3-1073 in 26 of 30 mice (86%) that persisted for at least 10 months. A second epitope (NS3-1169) was also recognized by cytotoxic and IFN-gamma-producing T cells, whereas a third one (NS3-1406) stimulated IFN-gamma production without cytotoxicity. The minimal amount of plasmid DNA required to induce CTLs was 2 ng. Upon challenge with recombinant HCV-NS3-expressing vaccinia virus, vaccinia titers were significantly lower in mice immunized with Salmonella-NS3 than in mice immunized with control Salmonella, demonstrating the in vivo function of CTLs. CONCLUSIONS: Oral immunization with attenuated Salmonella typhimurium as a carrier for HCV DNA induces long-lasting T-cell responses.

Administration, Oral↗
PubMed2001

Hepatitis C and the leptin system: bound leptin levels are elevated in patients with hepatitis C and decrease during antiviral therapy.

BACKGROUND: Serum leptin levels are elevated in alcoholic liver cirrhosis and thus might be involved in the anorexia and hypermetabolism often seen in those patients. We hypothesized that the leptin system is modulated in patients with hepatitis C and might be affected by antiviral therapy. The aim of this study was to investigate the different leptin components in serum of patients with hepatitis C before, during and after interferon alpha and ribavirin therapy and in controls. METHODS: 25 patients (11 female, 14 male) with chronic hepatitis C were compared with body mass index, gender and age-matched controls (n = 25). Patients were treated with interferon alpha alone (3 MU tiw) or in combination with ribavirin for 6-12 months. Free leptin and bound leptin levels were measured using specific radioimmunoassays before interferon therapy, at 12 weeks of therapy and after 3 months of follow-up. RESULTS: Free leptin levels were higher in female than in male subjects, both for patients (P < 0.01) and controls (P < 0.05). Bound leptin levels were elevated in both female (P < 0.05) and male (P < 0.001) patients compared to controls. No alteration of free leptin levels was found during therapy, whereas bound leptin levels decreased after 3 months of therapy (P < 0.005) and re-increased to the baseline levels 3 months after therapy was stopped. Responder but not non-responder had decreased bound leptin levels (P < 0.01) comparing pre- and posttreatment levels. However, no significant correlations were determined between any of the leptin components to virus load, ALT, TNF alpha receptor levels (sTNFR-75, sTNFR-55) and histopathology at any time point. CONCLUSION: Since no correlation was found between the different leptin components and any of the inflammatory markers, the decrease in bound leptin levels during antiviral therapy suggests either a direct interferon-dependent effect on the leptin system or an alteration of other leptin secretagogues.

Adult↗
PubMed2001

Cross-reactivity between hepatitis C virus and Influenza A virus determinant-specific cytotoxic T cells.

The cellular immune response contributes to viral clearance as well as to liver injury in acute and chronic hepatitis C virus (HCV) infection. An immunodominant determinant frequently recognized by liver-infiltrating and circulating CD8(+) T cells of HCV-infected patients is the HCV(NS3-1073) peptide CVNGVCWTV. Using a sensitive in vitro technique with HCV peptides and multiple cytokines, we were able to expand cytotoxic T cells specific for this determinant not only from the blood of 11 of 20 HCV-infected patients (55%) but also from the blood of 9 of 15 HCV-negative blood donors (60%), while a second HCV NS3 determinant was recognized only by HCV-infected patients and not by seronegative controls. The T-cell response of these healthy blood donors was mediated by memory T cells, which cross-reacted with a novel T-cell determinant of the A/PR/8/34 influenza A virus (IV) that is endogenously processed from the neuraminidase (NA) protein. Both the HCV NS3 and the IV NA peptide displayed a high degree of sequence homology, bound to the HLA-A2 molecule with high affinity, and were recognized by cytotoxic T lymphocytes with similar affinity (10(-8) M). Using the HLA-A2-transgenic mouse model, we then demonstrated directly that HCV-specific T cells could be induced in vivo by IV infection. Splenocytes harvested from IV-infected mice at the peak of the primary response (day 7 effector cells) or following complete recovery (day 21 memory cells) recognized the HCV NS3 peptide, lysed peptide-pulsed target cells, and produced gamma interferon. These results exemplify that host responses to an infectious agent are influenced by cross-reactive memory cells induced by past exposure to heterologous viruses, which could have important consequences for vaccine development.

Animals↗
PubMed2001

Genetic immunization of wild-type and hepatitis C virus transgenic mice reveals a hierarchy of cellular immune response and tolerance induction against hepatitis C virus structural proteins.

To study the effect of genetic immunization on transgenic expression of hepatitis C virus (HCV) proteins, we evaluated the immunological response of HCV transgenic mice to HCV expression plasmids. FVB/n transgenic mice expressing HCV structural proteins (core, E1, and E2) and wild-type (WT) FVB/n mice were immunized intramuscularly with plasmids expressing core (pHCVcore) or core/E1/E2 (pHCVSt). After immunization, HCV-specific humoral and cellular immune response was studied. Both WT and transgenic mice immunized with either HCV construct produced antibodies and exhibited T-cell proliferative responses against core or envelope. In WT mice immunized with pHCVSt, cytotoxic T-lymphocyte (CTL) activities were detected against E2 but not against core or E1, whereas strong CTL activities against core could be detected in WT mice immunized with pHCVcore. In pHCVSt-immunized, transgenic mice, CTL activities against the core or envelope were completely absent, but core-specific CTL activities could be detected in pHCVcore-immunized transgenic mice. A similar pattern of immune responses was also observed in other mouse strains, including a transgenic line expressing human HLA-A2.1 molecules (AAD mice). Despite the presence of a peripheral cellular immunity against HCV, no liver pathology or lymphocytic infiltrate was observed in these transgenic mice. Our study suggests a hierarchy of CTL response against the HCV structural proteins (E2 > core > E1) in vivo when the proteins are expressed as a polyprotein. The HCV transgenic mice can be induced by DNA immunization to generate anti-HCV antibodies and anticore CTLs. However, they are tolerant at the CTL level against the E2 protein despite DNA immunization.

Adoptive Transfer↗
PubMed2001

Induction of autoantibodies to the adrenal cortex and pancreatic islet cells by interferon alpha therapy for chronic hepatitis C.

BACKGROUND/AIMS: Interferon alpha (IFN-alpha) therapy for chronic hepatitis C may trigger induction of autoimmunity against several organs. Immune reactions against distinct adrenocortical protein antigens involved in adrenal autoimmune disease have not been reported to date. Therefore, we investigated the development of highly sensitive and specific adrenal autoantibodies in patients with chronic hepatitis C in response to IFN-alpha treatment. In addition, we studied induction of pancreatic islet and thyroid autoantibodies. PATIENTS/METHODS: Sera of 75 patients (42 males, 33 females; mean age 47 (13) years) were analysed before, during, and after IFN-alpha therapy (9-18x10(6) IE/week; mean duration 8.3 (3.5) months). Autoantibodies (Abs) to adrenal 21-hydroxylase (21OH-Abs), and to islet glutamic acid decarboxylase (GAD65-Abs) and protein tyrosine phosphatase (IA2-Abs) were determined by a radiobinding assay using (35)S labelled protein generated by an in vitro translation system. Thyroid antibodies were measured by a commercially available ELISA. RESULTS: Thirteen of 75 patients were initially positive for some of the autoantibodies. During or after IFN-alpha therapy, 3/62 initially negative patients (4.8%) developed 21OH-Abs. GAD65-Abs or IA2-Abs appeared in 5/62 and 1/62 patients, respectively (9.7% in total). In 12/62 patients (19.4%), thyroid specific antibodies appeared. In none of the 21OH-Ab positive subjects was adrenal dysfunction observed, and no patient with islet autoantibodies developed diabetes mellitus or impaired glucose tolerance. CONCLUSIONS: IFN-alpha induces 21OH-Abs in some cases, while islet and thyroid specific autoantibodies are more frequently found. However, our results indicate for the first time that the adrenal cortex also has to be considered as a potential target of IFN-alpha related autoimmunity.

Adrenal Cortex↗
PubMed2001

Current and future treatment of hepatitis C.

Hepatitis C virus infection is a major health burden affecting an estimated 200 million people worldwide. Chronic hepatitis C is one of the leading causes of cirrhosis and end-stage liver cirrhosis; thus effective therapies are required. For many years interferon-alpha has been the treatment of choice for patients with chronic hepatitis C infection. However, in only 10%-15% of patients is interferon-alpha monotherapy successful, leading to sustained virological response. A combination of interferon-alpha and ribavirin significantly enhanced sustained virological response rates to 40%. Strategies to further improve response rates include modification of the interferon dosing schedule with induction dosing and daily interferon, new interferons such as consensus interferon, or interferon with longer half-life and more favorable pharmacokinetics such as pegylated interferons. Recent trials showed that a combination of pegylated interferons and ribavirin leads to sustained response rates of about 50% with an acceptable safety profile. Hopefully, new treatment modalities will be available in the near future. Helicase, protease and the RNA polymerase are potential targets to suppress HCV replication and several immunotherapeutic approaches are explored.

Antiviral Agents↗
PubMed1999

Famciclovir treatment of chronic hepatitis B in heart transplant recipients: a prospective trial.

UNLABELLED: Hepatitis B may take a rapid and aggressive course in patients under immunosuppression. Nucleoside analogues have been shown to suppress viral replication effectively. To investigate the effect of famciclovir in immunosuppressed patients, 21 heart transplant recipients with chronic hepatitis B infection were included in a prospective study. PATIENTS AND METHODS: Patients have been treated with Famciclovir for a median of 14 months. Hepatitis B virus replication and biochemical parameters were regularly tested and liver biopsies were taken before treatment and after a median time of 7 months. HBV-polymerase was sequenced in all patients before therapy and in those patients who experienced virological breakthrough. RESULTS: Nineteen patients were treated for at least 6 months. Hepatitis B virus-DNA levels declined in all patients and became negative in 8 patients. Mean hepatitis B virus-DNA levels decreased from 199+/-269 to 34+/-53 pg/ml after 24 weeks (P=0.003). During treatment HBeAg became negative in five patients. Mean alanine aminotransferase decreased from 42+/-26 to 24+/-10 U/L (P=0.006). Histological analysis revealed improved inflammatory activity according to the Ishak-score in 11/16 (69%) patients. Total inflammatory activity scores decreased from 8 to 6 (median, NS), but interface hepatitis score (P=0.02) and lobular inflammation score (P=0.006) improved significantly. Median fibrosis scores fell from 5 to 3 (P=0.002). Three patients developed virological breakthrough on famciclovir after 7, 8, and 26 months of treatment showing HBV-polymerase amino acid changes L528 M, S567A, and I581K, respectively. CONCLUSIONS: Famciclovir improves not only biochemical and virological features but also hepatic inflammation and liver fibrosis in patients with chronic hepatitis B under heavy immunosuppression. Virological breakthrough may develop and requires close monitoring.

2-Aminopurine↗
PubMed1999

Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers.

It is believed that the hepatitis C virus (HCV)-specific CD8(+) cytotoxic T lymphocytes (CTLs) play a role in the development of liver cell injury and in the clearance of the virus. To develop a direct binding assay for HCV-specific CTLs, we generated two peptide-MHC tetramers by using the recombinant HLA A2.1 molecule and A2-restricted T cell epitopes of the HCV NS3 protein. With these reagents we are able to detect specific CD8(+) cells in the blood of 15 of 20 HLA-A2(+), HCV-infected patients, at a frequency ranging from 0.01% to 1.2% of peripheral CD8(+) T cells. Phenotypic analysis of these specific cells indicated that there is a significant variation in the expression of the CD45 isoforms and CD27 in different patients. A 6-hour incubation of one patient's blood with NS3 peptides resulted in the activation of the epitope-specific CD8(+) cells, as indicated by their expression of CD69 and IFN-gamma. We also detected NS3-specific CD8(+) T cells in the intrahepatic lymphocyte population isolated from liver biopsies of two HCV-infected patients. The frequency of these specific CD8(+) cells in the liver was 1-2%, at least 30-fold higher than in the peripheral blood. All of the intrahepatic NS3-specific CD8(+) T cells were CD69(+), suggesting that they were activated CTLs. Direct quantitation and characterization of HCV-specific CTLs should extend our understanding of the immunopathogenesis and the mechanism of clearance or persistence of HCV.

Antigens, CD↗
PubMed1999

Epitope mapping of cytochrome P4502D6 autoantigen in patients with chronic hepatitis C during alpha-interferon treatment.

BACKGROUND/AIMS: Cytochrome P450 2D6 (CYP2D6) has been documented as the major target antigen of liver kidney microsomal autoantibodies type-1 (anti-LKM-1) in both autoimmune hepatitis type-2 (AIH-2) and hepatitis C (HCV). In HCV/anti-LKM-1-positive patients, the choice between alpha-interferon (alpha-IFN) or immunosuppression may be difficult. This study was conducted to evaluate the course and outcome of alpha-IFN therapy in HCV/anti-LKM-1-positive and -negative patients and the alterations in these autoantibody titers by the indirect immunofluorescence and a novel radioligand assay. Epitope mapping was also performed to screen for a potential shift in anti-LKM-1 binding towards small linear epitopes, which are more often detected in AIH-2 patients. METHODS: Twenty-one patients with HCV infection received alpha-IFN. Seven patients were anti-LKM-1 positive (study group) and 14 patients were anti-LKM-1 negative (disease control group). Anti-CYP2D6 detection was based on immunoprecipitation of [35S]-methionine-labeled CYP2D6 recombinant protein (rCYP2D6) produced by in vitro transcription/translation. RESULTS: Four out of seven (57%) patients in the study group and 5/14 (36%) in the disease control group initially responded, but subsequently relapsed. During follow-up, alanine aminotransferase significantly increased in the study group compared to the disease control group (p<0.01). A slight increase, followed by a plateau of autoantibody titers was recorded by the radioligand assay and by indirect immunofluorescence during therapy and follow-up in most cases. In one patient, however, gamma-globulins and anti-LKM-1 titers increased, reaching very high levels (1:40 960). alpha-IFN was interrupted and immunosuppression was started. HCV/anti-CYP2D6 positive sera recognized CYP2D6 expressed in E. coli and two truncated proteins (aa 250-494 and 321-494). Two out of seven sera, in addition reacted with a small linear epitope of aa 257-269 (one of which also reacted with a C-terminal domain of aa 350-494). CONCLUSIONS: A rather mild deterioration in liver disease was observed in only 1/7 HCV/anti-LKM-1-positive patients during alpha-IFN treatment. This patient showed high anti-CYP2D6 titers before the initiation of therapy, a sharp increase in anti-LKM-1 titers during treatment, and reactivities to a small linear epitope and an infrequently recognized C-terminal domain of CYP2D6. After switching to immunosuppressive treatment, a complete and sustained response was recorded. Further prospective studies from many centers are needed to define whether these features have general, clinical significance or not.

Adolescent↗
PubMed1998

Long-term outcome of chronic hepatitis B in heart transplant recipients.

BACKGROUND: Hepatitis B is common in organ transplant recipients. It adversely affects the prognosis after liver and kidney transplantation. The long-term outcome of hepatitis B virus (HBV) infection in heart transplant recipients has not been studied before. METHODS: Between July 1984 and June 1993, 436 patients underwent heart transplantation at the Hannover Medical School. A total of 345 patients survived for more than 1 year and were included in this study. Of these, 74 were found to be hepatitis B surface antigen (HBsAg)-positive during follow-up; 69 acquired HBV infection at known time points 25+/-17 months after transplantation, and 5 had already been infected before heart transplantation. Mean follow-up was 105 (range, 25-157) months. RESULTS: Patients developed significant alanine aminotransferase (ALT) elevations after HBV infection, which peaked and then remained above normal. Preinfection levels of ALT were 15.4+/-6.4 U/L, peak values were 71.2+/-47.2 U/L, and mean values after HBV infection were 28.9+/-14.6 U/L. All patients remained HBsAg-positive. Thirteen patients (18%) became HBeAg-negative during follow-up, 10 with negative quantitative HBV-DNA assays. Mean HBV-DNA levels in the remaining patients were 292+/-267 (range, 0-978) pg/ml. Thirty-four patients died during follow-up (45.9%) compared to 78/271 (28.8%) in the control group (P=0.008). Six of the HBsAg-positive patients (17.1%) died of liver failure 6.2-10.6 years (mean, 8.6) after transplantation. Histology of 25 HBsAg-positive patients more than 5 years after infection revealed severe fibrosis or cirrhosis in 14 (56%), mild fibrosis in 9 (36%), and chronic hepatitis without fibroproliferation in 2 (8%). CONCLUSIONS: Hepatitis B infection after heart transplantation leads to chronic liver disease in the majority of the affected patients, causing cirrhosis in more than 55% within the first decade after transplantation. Liver failure is a common cause of death in the infected group of patients. Active HBV vaccination is mandatory for all organ transplant candidates, in particular before heart transplantation.

Adult↗
PubMed1998

[Significance of coinfection with hepatitis G virus for chronic hepatitis C--a review of the literature].

BACKGROUND: The clinical significance of the recently discovered hepatitis C virus (HGV/GB virus C (GBV-C) is not conclusively clarified. The aim of this analysis was to evaluate the frequency of HGV/GBV-C coinfection at existing hepatitis C infection, the significance for the course of the liver disease, and its response to antiviral therapy. METHODS: The literature available by medline and the PubMed Retrieval System as well as abstracts of recent German, European, and American conferences on liver diseases (GASL, EASL, ASSLU) concerning HCV/GBV-C-coinfection were analyzed. RESULTS: We identified 66 references with 5,388 patients suffering from HCV-infection. 941 (17.5%) were coinfected with GBV-C. Excluding some groups at risk (intravenous drug abusers, dialysis patients, patients after liver transplantation), the rate of coinfection varied significantly in respect to geography: 20.5% in European vs. 10.9% in Japan (p < 0.0001). Additionally, coinfection occurred in 38% of intravenous drug users. The studies showed that coinfection was related to the frequency of blood transfusions. Furthermore, the parenteral transmission route of GBV-C was generally confirmed. Overall GBV-C does not seem to have any negative influence on the course of HCV-related chronic liver disease or the development of chronicity of acute hepatitis C infection, nor does it have any influence on histology, transaminase-levels or response of HCV to antiviral therapy; GBV-C was shown to be sensitive to interferon-alpha with a relapse rate up to 53% comparable to HCV. There is no correlation between response of HCV and GBV-C to interferon. CONCLUSION: This analysis of the published data concerning coinfection of HCV and HGV/GBV-C revealed no influence of GBV-C on the course of HCV-related liver disease (clinical, biochemical, histological). GBV-C does not modify the response rate of HCV to interferon-alpha, but GBV-C is sensitive to interferon with high relapse rates.

Flaviviridae↗
PubMed1998

[Is combination therapy of chronic hepatitis C with interferon alpha and ribavirin in primary interferon nonresponders indicated?--An analysis of personal experiences and review of the literature].

Combination therapy of chronic hepatitis C with interferon alpha and ribavirin has been proven to be highly effective in naive and relapse patients with two to ten-fold increase of the response rate. However, combination therapy of primary non-responders to interferon alpha is discussed controversially. Therefore, to analyze the response rate to retreatment with a combination therapy with interferon alpha and ribavirin, we compared data of 555 patients described in 23 publications to the data of 16 non-responders treated in our center. The patients received interferon alpha (at least 3 MU tiw) and ribavirin in a dose of 1,000/1,200 mg per day. At the end of treatment 14% of our patients had normal ALT values and were HCV-RNA-negative compared to 34% of all patients described in the literature. In our patients the viral load decreased from 1,110 +/- 670 x 10(3) copies/ml prior to therapy to 300 +/- 480 x 10(3) copies/ml at the end of treatment (p = 0.002). After a follow-up period of six months quantitative RNA-levels rose again to 1,485 +/- 755 x 10(3) copies/ml. Whereas only 7.4% (24/325) of all patients described showed a response with normal ALT values and negative HCV-RNA at the end of follow-up, no sustained response was observed in our patients. In contrast to naive and relapse patients, the response rate of combination therapy in patients previously not responding to interferon alpha alone is only low. Thus, standard regime (IFN 3MU twi plus ribavirin for six months) as a regular therapy for non-responders is not recommended.

Adult↗
PubMed1995

Chemosensitivity of the osphradium of the pond snail Lymnaea stagnalis

The osphradium of the pond snail Lymnaea stagnalis was studied to determine the stimuli to which this organ responds. The following stimuli were tested: hypoxia, hypercapnia, a mixture of amino acids, a mixture of citralva and amyl acetate and a mixture of lyral, lilial and ethylvanillin. The mean nerve activity consistently increased with elevated PCO2, whereas hypoxia produced variable effects. The nerve activity became rhythmic upon application of citralva and amyl acetate, but it increased in a non-rhythmic way upon application of the other two odorant mixtures tested. Whole-cell patch-clamp recordings were made from a group of 15 neurones that lay next to the issuing osphradial nerve, to determine whether ganglion cells were involved in olfactory signal processing. All neurones tested responded to at least one of the three mixtures of odorants. Both excitatory and inhibitory responses occurred. Our results indicate that the osphradium of the pond snail Lymnaea stagnalis is sensitive to elevated PCO2 as well as to three different classes of odorants. In addition, at least some neurones within the osphradium are involved in the processing of olfactory information.

Journal Article↗
PubMed1990

Concerns of a pediatric hospital's P & T Committee: quality care emphasized over cost considerations.

One of the greatest challenges faced by the P & T Committee at Children's Hospital of Denver--a full-service, regional pediatric referral center--is the absence of pharmacologic and pharmacokinetic data for many drugs that are on the market for the treatment of adults but are unapproved for pediatric use. To acquire the needed information, Children's Hospital will rely on its P & T Committee to conduct numerous drug usage evaluations. In addition, the committee is undertaking a cooperative data-exchange venture with other children's hospitals across the U.S. and Canada. Although cost issues must be addressed at Children's Hospital, issues such as quality of care--and even how various formulations taste--are top priorities at this hospital.

Child↗