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Hungarian Immunology

OCTOBER 10, 2005

[Plasmacytoid dendritic cells - type I interferon producing cells]

MAGYARICS Zoltán, RAJNAVÖLGYI Éva

[Dendritic cells represent a multifunctional cell population classified to myeloid (mDC) and plasmacytoid (pDC) types. Both subsets circulate in the peripheral blood and are found in lymphoid and also in non-lymphoid tissues, where they act as sensors of environmental changes. Upon activation by a wide range of stimuli they undergo morphological and functional transition and give rise to professional antigen presenting cells, which migrate to lymphoid organs. A newly identified precursor subset of human dendritic cells has recently been identified as professional type I interferon producing cells (IPC) with multiple functional activities. With their capacity of priming, instructing and regulating various pathogen- and tumor-specific immune responses, IPC/pDC act as a link between innate and adaptive immunity. The role of pDC in the pathogenesis of various diseases is well established, and these cells also emerge as novel candidates of immunomodulation.]

Lege Artis Medicinae

NOVEMBER 19, 2006

[TREATMENT APPROACHES OF CHRONIC HEPATITIS B IN HUNGARY]

TORNAI István, NEMESÁNSZKY Elemér

[Today, there are less patients with active chronic hepatitis B requiring treatment than patients with chronic hepatitis C. However, the course and outcome of chronic hepatitis B is usually more severe, therefore, the disease has not lost importance. The most dangerous risks are the development of liver cirrhosis and hepatocellular carcinoma. The disease may present in various forms. Symptom-free carriers only need follow-up and hepatologic care. In the active stages with elevated liver enzymes and high level of viral nucleic acid (either HBeAg negative or positive), however, antiviral treatment is strongly indicated. There are two main forms of treatment. Alfa-interferon-based therapy, which is applied for a defined period of time, has a direct antiviral and immunomodulatory effect, but has several adverse effects. Long-term nucleoside analogue treatment represent the other treatment modality. These drugs are administered orally, have minimal side effects, but after some time resistant mutants may develop. Traditional interferon has recently been replaced by pegylated interferon alfa-2a with much better pharmacokinetic properties. Lamivudine has been in use for the longest time of the nucleoside analogues. Its efficacy is high, but after 3 to 4 years of treatment, resistant mutants appear in about 70% of cases. Of the most recent compounds, adefovir dipivoxil has recently become available in Hungary; it is primarily recommended in cases with lamivudine resistant mutants. There are promising new drugs in the stages of clinical trial; of these, entecavir has already been approved in the United States.]

Lege Artis Medicinae

SEPTEMBER 20, 2002

[Drug treatment possibilities in chronic liver diseases]

HAGYMÁSI Krisztina, LENGYEL Gabriella, FEHÉR János

[Alcoholic and drug induced liver diseases, nonalcoholic steatohepatitis, hepatitis C and B chronic hepatitis, autoimmune diseases (primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis) and metabolic disorders (hemochromatosis, Wilson's disease) are the main chronic liver diseases. Authors summarize, based on the latest literature data, the medications of chronic liver diseases, emphasizing the treatment of the everyday practice. Natural and synthetic antioxidants are approved for the treatment of chronic alcoholic liver diseases besides abstinence, with diet of adequate quality and quantity. Nucleoside analogues (lamivudin) are recommended for the first-line therapy of the treatment of chronic hepatitis B. Interferon is presently considered the optimal treatment for only certain patients. Interferon and ribavirin combined therapy is well-established in the treatment of chronic hepatitis C. Ursodeoxycholic acid is the beneficial treatment option for primary biliary cirrhosis and primary sclerosing cholangitis. Prednisolon and azathioprine constitute the basic therapy of autoimmune hepatitis. Presumably, in the future, new strategies based on immunosuppressive combinations will play a crucial role. The chelating deferoxamine has less important part in the treatment of hemochromatosis. D-penicillamine still plays principle role in the medication of Wilson's disease.]

Lege Artis Medicinae

MAY 26, 2008

[RETREATMENT OF CHRONIC HEPATITIS C IN PREVIOUS NONRESPONDERS]

TORNAI István

[Only approximately 50% of patients with chronic hepatitis C virus (HCV) genotype 1, the prevailing genotype in Hungary, show a sustained virologic response (SVR) when treated with the combination of peginterferon alfa and ribavirin. The number of patients who do not respond to this treatment is continuously increasing. The appearance of increasingly efficient treatment modalities was seen in the past 15 years, but now no new drugs are expected for a few years. There is a growing need for retreatment to prevent possible progression of the disease. The best candidates for retreatment are identified based on the data of the previous treatment; the dosage of the drugs used, dose reductions and their causes, the kinetics of the virologic response, the patient’s compliance, and every correctable and non-correctable factor should be carefully analysed. When the previous treatment with peginterferon and ribavirin failed to induce response, retreatment is only recommended if correctable factors can be identified. Repeated treatment may result in sustained virologic response usually if a longer duration and/or higher dose of ribavirin is applied. Since the best possible outcome of retreatment is sustained virologic response in 10 to 30% of patients, which is significantly lower than the results achieved in naive patients, every effort has to be made to increase the efficacy of the first treatment. For patients in whom no sustained virologic response can be achieved, a maintenance therapy with low dose interferon may be considered, although its benefit is yet to be proven. New small molecules are under development, which may bring further hope for nonresponders to current standard therapy.]

Lege Artis Medicinae

MAY 20, 2004

[NEUROFIBROMATOSIS, MALIGNANT MELANOMA AND HYPERTHYREOIDISM IN A HCV POSITIVE PATIENT]

FOLHOFFER Anikó, HORVÁTH Andrea, CSÁK Tímea, NÉBENFÜHRER László, TELKES Márta, IVÁNYI András, SZALAY Ferenc

[INTRODUCTION - Similar occirrence of neurofibromatosis and malignant melanoma is rare. We report a patient with neurofibromatosis, cutaneous melanoma, hyperthyreoidism and HCV positivity. CASE REPORT - A 43-year-old woman has been under care for neurofibromatosis for 16 years when she presented with increased serum ?- glutamyltransferase, alkaline phosphatase activity and anti-HCV antibody positivity at regular checkup. A pigmented lesion removed from her back histologically proved to be cutan melanoma. Interferon treatment was applied. She lost 8 kilograms in half a year which was caused not by the tumor progression, but hyperthyreoidism. A rapid clinical and laboratory improvement was observed for thyreostatic treatment and she regained her bodyweight. One year later she presented with a cough caused by pulmonary tumor. The tumor was surgically removed and histologically diagnosed as metastasis of melanoma. Cytostatic treatment was applied and she became asymptomatic. Four years after the diagnosis of melanoma she died of apoplexy. During the autopsy there was no sign of either melanoma or liver disease. CONCLUSIONS - The careful investigation of skin should be emphasised even in case of long established neurofibromatosis. The presented case shows an association of malignant melanoma and neurofibromatosis. In the background of loss of bodyweight even in a patient with history of malignant disease other causes should also be searched such as hyperthyreoidism especially during interferon therapy.]

Clinical Neuroscience

NOVEMBER 30, 2006

[LONG-TERM APPLICATION OF THE MULTIPLE SCLEROSIS FUNCTIONAL COMPOSITE IN DEBRECEN]

MEZEI Zsolt, BERECZKI Dániel, CSIBA László, CSÉPÁNY Tünde

[Introducion - The multiple sclerosis functional composite (MSFC) has been recommended by the National Multiple Sclerosis Society as a new clinical outcome measure. It is based on measurements in three clinical dimensions: leg function/ambulation (timed 25-foot walk), arm function (9 hole peg test) and cognitive function (paced auditory serial addition test). Scores on component measures are converted to standard scores (Z-scores), that reflect patient performance. This method has not yet been introduced into routine clinical practice. Patients and methods - Since March 2000 over the five years period the MSFC calculation was applied to 17 patients with relapsing-remitting multiple sclerosis (age mean: 37.4±10.8 years, duration of the disease: 5.5±4.9 years, EDSS: 2.7±1.4) seen at the neuroimmunological outpatient clinic to evaluate its usefulness and its correlation with the traditionally applied expanded disability status scale (EDSS). Thirteen patients received immunomodulatory treatment (interferon beta and glatiramer acetate), one patient received immunosuppressant therapy (azathioprine), and there was a patient, to whom developed secondary - progressive phase and we changed the interferon treatment to mitoxantrone. MSFC and EDSS were measured at 3., 6., 9, 12., 18 and 60 months of follow-up. Results - The prospective study confirmed a strong correlation between EDSS and MSFC in multiple sclerosis. The MSFC was more sensitive to clinical changes than EDSS. Our results after 18 months of follow up are already published. After five years arm/hand function and leg function/ambulation were the most sensitive mesures for disease progression. In contrast with the literature we did not experience correlation with cognitive changes. Consequences - We demonstrated strong correlation between MSFC and EDSS after a longer period. MSFC is a simple method, suitable for follow-up of multiple sclerosis patients in everyday clinical practice.]

Hungarian Immunology

MARCH 20, 2002

[Neonatal activation of interferon-γ in macrophages]

ERDŐS Melinda, MARÓDI László

[Each individual passes through developmental or transient immunodeficiency due to the immaturity of the immune system in early childhood, expecially in the neonatal period. Therefore, neonates contract infections by intracellular and extracellular microorganisms more easily than older children and adults, and develop more severe disease with a high mortality rate. A number of abnormalities in the neonate’s host defense systems have been described suggesting that the immune system at birth functionally differs from that in adults. Neonatal T and B cells show decreased reactivity to antigens and mitogens and have deficienct IgM-IgG isotype switching. Newborns have decreased functional capacities of the hemolytic complement system. Under the same in vitro and in vivo conditions neonatal granulocytes show functional deficiency earlier than adult cells. Effector mechanisms of the cell-mediated immunity involve activation of macrophages by T helper1 cytokines, particularly interferon- γ (IFN-γ). IFN-γ is the most important macrophage-activating cytokine in vivo. Neonatal T cells express lower levels of IFN-γ and macrophages are hyporesponsive to activation by this cytokine. This deficiency may be explained by decreased phosphorilation of STAT1 despite comparable expression of STAT1 protein in neonatal and adult macrophages.]

Lege Artis Medicinae

NOVEMBER 20, 2007

[OUR EXPERIENCE WITH COMBINED ANTIVIRAL TREATMENT IN PATIENTS WITH CHRONIC HEPATITIS C WITH PERSISTENTLY NORMAL ALANINE AMINOTRANSFERASE LEVELS]

HORVÁTH Gábor, TOLVAJ Gyula, HALÁSZ Tünde, STOTZ Gyula

[INTRODUCTION - Persistently normal alanine aminotransferase levels, which occur in a fraction of patients chronically infected with hepatitis C virus, do not rule out the presence of chronic hepatitis C, even of that with advanced inflammation and fibrosis. Here we report our results of the treatment of these patients. PATIENTS AND METHODS - Patients with histologically confirmed chronic hepatitis C received combined antiviral treatment with pegylated interferon (alfa-2a 1×180 μg/week or alfa-2b 1×1.5 μg/kg/week) and ribavirin (800- 1200 mg/day) for 48-52 weeks. The alanineaminotransferase levels of 21 patients (14 females, 7 males, age: 20-54, mean 38 years) did not reach the upper limit of normal (40 U/l) during the period of observation (≥6 months). There were 19 and 2 cases with hepatitis C virus genotype 1b and 3, respectively. The patients' hepatitis activity index was 3.7 1.75, fibrosis score: 0.9 0.64, baseline viral titer: 1.18 1.12×106 IU/ml, alanine-aminotransferase level: 33.51 7.2 U/l. The last 100 unselected patients with elevated alanine-aminotransferase levels enrolled in treatment for chronic hepatitis C and who were followed for at least 6 months served as the control group with the following parameters: 41 females and 59 males (age: 18- 65, mean: 45.65 years), viral genotypes: 98 and 2 cases of type 1 and 3, respectively, hepatitis activity index: 5.44±4.03, stage: 1.29±1.00, baseline viral titer: 4.13±6.25×106 IU/ml. RESULTS - In the study group, all patients were hepatitis C virus RNA negative at the end of the treatment and with one exception remained so by the end of the 6-month follow-up period (20/21), while the sustained virologic response was 36% in the control group. The pretreatment normal alanine aminotransferase level decreased significantly (15.26 4.9 vs 33.51 7.2 U/l, p<0.001) by the end of the treatment, and remained at this level during the follow-up in all except one relapse case. CONCLUSION - The efficacy of the combined antiviral treatment is high in patients with persistently normal alanine aminotransferase levels, possibly due to the relatively younger age, the higher proportion of females, the lower baseline viral titer, and the less advanced liver disease (lower inflammatory activity and less or absent fibrosis) observed in this group. Combined antiviral treatment is recommended for patients with histologically confirmed chronic hepatitis C with normal alanine aminotransferase levels, even with mild inflammatory activity and minimal or absent fibrosis in the liver tissue. The previous suggestions based on published evidence to revise the upper limit of the normal range of alanine aminotransferase level are supported by the results of this study.]

Lege Artis Medicinae

NOVEMBER 10, 2008

[UP-TO-DATE MANAGEMENT OF CHRONIC HEPATITIS B]

HORVÁTH Gábor

[Hepatitis B virus infection is a significant health problem worldwide, as well as in Hungary. The chronic infection is usually symptomless, its most dangerous risks are liver cirrhosis and hepatocellular carcinoma. The latter may occur without development of liver cirrhosis, so it means a potential complication for patients with inactive phase of infection, as well. Criteria of the indication of antiviral treatment have changed in the last years due to the flare of our knowledge about the natural history of the disease. In our days quantitative determination of hepatitis B viral nucleic acid titer is essential for diagnosis. Formerly, a HBsAg positive patient with normal liver enzymes had been regarded as inactive carrier, and antiviral treatment had not been advised. In our days, the phase of the infection and the necessity of the treatment can not be determined without measurement of nucleic acid titer. Liver biopsy and, if inflammation or fibrosis is present, antiviral treatment is indicated, if the nucleic acid titer is >20 000 IU/ml in HBeAg positive, and >2000 IU/ml in HBe negative cases, respectively. Interferon alpha is the gold standard of treatment for chronic B hepatitis. Pegylated interferon alpha-2a is used because of its better pharmacokinetic properties. Oral agents include nucleoside/ nucleotide analogues with rare and mild adverse effects, and they may be given to patients with decompensated liver disease. Their main disadvantages include the development of drug-resistance, and the very low ratio of HBsAg-anti-HBs seroconversion. Recent drugs like adefovir, entecavir and tenofovir have replaced lamivudin, which has been in use for the longest time, because they are more effective and resistance against them is less frequent.]

Clinical Neuroscience

MAY 30, 2006

[IMPORTANCE OF THE ANALYSIS OF NEUTRALIZING ANTIBODIES TO IMMUNOMODULATORY THERAPY DURING TREATMENT OF MULTIPLE SCLEROSIS]

SERES Erika, VÉCSEI László

[Interferon-α, -β, and -γ have been used for the management of several diseases with varying clinical effects. Like many other proteins, all interferon species are potentially immunogenics especially those produced by recombinant gene technologies. A reliable screening assay for anti-interferon-β antibodies is suggested for patients with multiple sclerosis receiving interferon-β therapy. Natural interferon-β is a glycosylated 166 amino acid 25 kDa protein, recombinant interferon-β is available for therapy as 1a and 1b products. Both preparations induce anti-interferon-β antibodies, detectable in the serum of interferon-β-treated patients with multiple sclerosis. The question of wich assay is optimal for testing for antiinterferon- β antibodies in interferon-β-treated patients is unsettled. Two types of antibody assays are generally used: those measuring binding antibodies and those measuring neutralizing antibodies. The findings suggest that high titers of both binding and neutralizing antibodies reduce the clinical efficacy of interferon-β in relapsing-remitting multiple sclerosis, which is important for the long-term efficacy of these drugs. Treatment with glatiramer acetat has also been shown to induce the development of “reactive antibodies” in patients with multiple sclerosis. This article briefly describes some of the findings concerning anti-interferon binding and neutralizing antibodies.]