A cellularis immun-tényezők vizsgálata gyermekkori praediabeteses állapotban. = Investigation of cellular immune-factors in prediabetic children.

Az 1-es típusú diabetes mellitus (T1DM) egy szervspecifikus autoimmun betegség, mely kialakulásának pontos folyamata mindmáig tisztázatlan. Az inzulintermelő béta-sejtek pusztulásáért elsősorban a gyulladásos reakciók felelősek. A kórlefolyás során szövettanilag szigetsejt gyulladás észlelhető és a betegek szérumában szigetsejt-alkotórészek elleni ellenanyagok jelennek meg. A pályázat keretében több, egymástól független vizsgálatot végeztünk el. Célunk volt különböző gyulladásos faktorok, illetve mechanizmusok és az T1DM közötti összefüggés megismerése. 1.A perifériás vér egyes fehérvérsejtjeinek aktivációs készségét vizsgálva prediabetesben a Th1/Th2 citokin (különböző gyulladásos folyamatot szabályozó fehérjék) arány emelkedését találtuk. 2.Kimutattuk, hogy az interleukin-6, tumor necrosis factor-alfa és interleukin-1-béta elnevezésű gyulladásos fehérjék befolyásolhatják a cukorbetegség kialakulásának idejét. 3.A hősokk fehérje (HSP) elnevezésű, a gyulladásos folyamat ellen ható faktor genetikai polimorfizmusának meghatározása során azt találtuk, hogy az alacsonyabb HSP elválasztással járó genotípus jelenléte a T1DM kialakulására hajlamosít. 4.A T1DM-re való genetikai hajlamot hordozó újszülöttek köldökzsinór vérének vizsgálata során a regulátor T-sejt asszociált FoxP3 transzkripciós faktor csökkent expresszióját mutattuk ki. A vizsgált faktornak az immuntolerancia kialakításában van szerepe, így hiánya az T1DM-re való hajlam egyik összetevője lehet. | The pathogenesis of type 1 diabetes mellitus (T1DM) is explained by the autoimmun insulitis, which results the gradual apoptosis of the pancreatic islet cells. Inflammatory mediators and cytotoxic T-lymphocytes may play a central role in the pathogenesis. During insulitis specific autoantibodies are detectable in peripheral blood. We aimed to investigate associations between inflammatory factors, inflammatory reactions and the development of T1DM. 1.We studied the activation ability of peripheral lymphocytes and found that the Th1/Th2 ratio was elevated in prediabetics. 2.We determined inflammatory citokines, named: interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF) and interleukin-1-beta (IL-1) genetic polimorphisms in T1DM children. We found that the age at the onset of T1DM was associated with the studied polymorphisms. 3.Heat shock protein (HSP)-72 is known to be an anti-inflammatory protein. We determined HSP-72 genetic polymorphism in T1DM children and found that lower HSP-72 producer genotype was associated with increased risk of T1DM. 4.We found reduced expression of regulatory T-cell associated transcription factor FoxP3 in cord blood T lymphocytes from newborn infants at genetic risk of T1DM. FoxP3 play a role in the development of immune tolerance and relative deficiency of FoxP3 may play a role in the development of autoimmune diseases, like T1DM

Rheumatic symptoms in childhood leukaemia and lymphoma-a ten-year retrospective study

Background: The initial symptoms of childhood leukaemia and lymphoma are often similar to those of juvenile idiopathic arthritis (JIA). In our study, we analyzed the frequency and characteristics of musculoskeletal complaints as the initial presenting symptoms of newly diagnosed leukaemia and lymphoma patients in the past 10 years in our clinic. Methods: Using the Hungarian Tumour Register, we performed a retrospective analysis of the medical records of 166 new leukaemia and 95 new lymphoma pediatric patients treated from 1999 to 2009 at the 2nd. Dept. of Paediatrics of the Semmelweis University in Budapest. Results: Twenty percent of the leukaemic (33 children) and 2% of the lymphoma patients (2 children) had musculoskeletal symptoms at first presentation. Two-thirds of both groups of patients had other general symptoms like fever and/or fatigue. The hip was the most frequently affected joint (7/33) in the leukaemic patients. Twenty-four percent of all the children had been previously evaluated by an orthopaedist; 12% had visited another rheumatologist prior to diagnosis. Imaging had been done in an unexpectedly low number of patients prior to referral to our unit (radiographs: 16 or 48%, ultrasound: 5 patients or 15%). Radiographs of the affected joints were abnormal in only one case (1/16, 6%). The joint ultrasound was abnormal in only three children of 5 studied (3/5, 60%). Anaemia (26/32, 6%), thrombocytopenia (78%) and LDH elevation (3-4 times the normal count) were frequent in the leukaemic patients. Half of the cases had a normal leukocyte count. The lymphoma group had similar results. Two patients of the leukaemia group received steroid treatment before the final diagnosis. Severe pain out of proportion to physical findings is another clue. Conclusions: Haematologic malignancies must be excluded before initiation of therapy for childhood arthritis among children presenting with musculoskeletal signs and symptoms, particularly in atypical cases. Malignancies are to be suspected when pain is disproportionately severe compared to the physical examination findings, and when anaemia, thrombocytopenia, and an elevated LDH level are present. Diagnosing leukaemia early is important because the use of steroids and immunosuppressive medications may mask and delay its diagnosis. Additionally, pre-treatment of presumed JIA patients with these drugs who eventually are diagnosed to have a malignancy may lead to the malignancy being steroid-resistant and more difficult to treat

Allergia genomika: ismert és teljes genomszűréssel kiemelt asthmára hajlamosító gének vizsgálata emberben és transzgenikus állatmodellen valamint európai összevetésre alkalmas hazai asthma biobank létrehozása = Allergy genomics: Studies on known and other asthma susceptibility genes found by whole genome search in human and transgenic animal models; generation of Hungarian asthma biobank for European comparative studies

A munka során egérmodellen és emberi mintákon allergiagenomikai (ezen belül asztmagenomikai) kutatást végeztek. Ennek során: 1. az allergiás immunválaszban szerepelő egyes molekulák génjeiben polimorfizmusokat (SNP) találtak, melyek szorosan kapcsoltak a betegséggel; 2. microarray (chip) génexpressziós analízissel az allergiás folyamatban kulcsszerepet játszó hízósejtekben eddig nem ismert géneket azonosítottak. Figyelmük elsősorban a hízósejt proteázaira irányították, ezek funkciója ugyanis kitekintést ad a hízósejt-tumor kölcsönhatásra is; 4. Létrehozták a hazai asztma biobankot és bekapcsolódtak a nemzetközi biobank hálózatba; 5. Kialakítottak egy egér asztmamodellt, amelyen részben igazolták a hisztamin szerepét az asztmában, másrészt új géneket azonosítottak az asztma patomechanizmusában; 6. Az állatkisérletek alapján az emberi genomban funkcionálisan jellemezték homológ géneket; 7. új RNS interferenciára (siRNS) alapuló asztma génterápia beállítását kezdték el. | In our work we carried out allergy -genomics (asthma-genomics) studies on murine model and human samples. The results include: 1. Finding genetic polymorphisms (SNP) related to the disease in the genes of molecules involved in allergic immune response; 2. Applying microarray (chip) gene expression analysis new (formerly unknown) important genes were identified. The attention has been focused on mast cell proteases, related to mast cell tumour interactions; 4. A Hungarian asthma biobank has been established and connected into the international biobanking network; 5. A murine asthma model has been generated, serving for examining the role of histamine in asthma and identification of novel genes in pathomechanism of asthma; 6. Based on animal models, homologous genes were characterized in human genome; a new gene therapy based on siRNS technology has been started

Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies

A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2-67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0.022/patient-year, P /= 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0.101 event/infusion. The incidence of local related AEs was 0.069 event/infusion (0.036 event/infusion, when excluding a 13-year-old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0.032 event/infusion. Most related AEs were mild, none were severe. For 64.6% of patients and in 94.8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0.95 (range = 0.3-4.1) h using mainly one to two administration sites [median = 2 sites (range = 1-5)]. Almost all infusions (99.8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment

Tolerability of subcutaneous immunoglobulin 20%, Ig20Gly, in pediatric patients with primary immunodeficiencies

Aim: To assess Ig20Gly tolerability in pediatric patients with primary immunodeficiencies. Patients & methods: Infusion parameters and tolerability were analyzed in pediatric patients (aged 2-5 years [n=6], 6-11 years [n=22] and 12-17 years [n=22]) receiving Ig20Gly in two Phase II/III trials. Results: Of 2624 Ig20Gly infusions, >99% did not require any rate reduction, interruption or discontinuation due to adverse events (AEs). Median maximum infusion rates and volumes/site were higher in patients 12-17 years of age (30ml/h/site; 30ml/site) versus 6-11 years (20ml/h/site; 15ml/site) and 2-5 years (18ml/h/site; 14ml/site). Rates of causally related systemic and local AEs (0.009 and 0.063 AEs/infusion) were low. Conclusion: Ig20Gly infused at relatively high rates and volumes was well tolerated in children