Projects / Programmes
SYSTEMIC IMMUNE-MEDIATED DISEASES IN CHILDREN AND ADOLESCENTS II
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| B660 |
Biomedical sciences |
Pediatrics |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
Pediatric antiphospholipid syndrome, Pediatric systemic lupus erythematosus, Vaccination, Pharmacogenetics, Inherited immune deficiencies
Researchers (19)
Organisations (3)
Abstract
Systemic immune-mediated diseases are one of the most common chronic illnesses of children and an important cause of short- and long-term disability. In addition to the complications that can occur in adults, specific concerns such as those related to growth, development, childhood vaccinations and quality of life characterize the disease in pediatric patients.
The proposed research project is a continuation and part of permanent basic and clinically applied research of pediatric systemic immune-mediated diseases at the University Children’s Hospital Ljubljana, which is oriented towards finding better diagnostic procedures for early detection of systemic immune-mediated diseases in children and their successful treatment. The project will focus on the following clinical conditions in children and adolescents:
1. Pediatric antiphospholipid syndrome and systemic lupus erythematosus
Based on literature data and personal experience obtained on treating children with elevated antiphospholipid antibodies (aPL), we believe that there are some important differences in pathophysiology and clinical spectrum of the APS related to the age at onset of the disease. Investigations in the present research proposal are designed to elucidate factors specific to children and to examine the clinical significance and pathogenic mechnisms of aPL in the pediatric population. It is expected that periodic analysis of the data from the international registry of pediatric APS will enable us to determine impact of treatment and long-term outcome of pediatric APS and to develop a consensus criteria for the classification of pediatric APS. In addition, we will monitor T cell signaling pathways of cytokines, important for their homeostasis and function, in pediatric patients with SLE and APS. We will use monitoring of signaling pathways and discovered phospho-signatures in develoment of new diagnostic tools, especially in monitoring of disease activity. Finally, the results of our studies may point to new targets of more specific and less toxic therapy in SLE and APS, for example with kinase inhibitors.
2. Autoimmune responses after vaccinations
In the proposed study we will evaluate long-term safety and efficacy of influenza vaccination in healthy subjects and a group of children with juvenile idiopatic arthritis (JIA) on immunosupressive medications. It is expected that this study will provide more reliable data on the safety and efficacy of influenza vaccination in healthy adults and in children with JIA and will contribute evidence-based data to the scientific and public debate on the role of influenza vaccination.
3. Mechanisms of drug interactions in pediatric systemic immune-mediated diseases
In the proposed study we will evaluate the formation of anti-drug antibodies in pediatric patients with rheumatic diseases treated with various biologic agents such as infliximab, adalimumab and etanercept. It is suspected that the formation of anti-drug antibodies is associated with altered pharmacokinetics of the biologics, therefore we will also monitor the serum trough levels of the drugs and correlate them with therapeutic efficacy. In the second part of this study we plan to determine genetic markers for efficacy and toxicity of JIA treatment and to conduct a clinical pharmacogenetic model to improve the treatment efficacy in children with JIA.
4. Inherited immune deficiencies – periodic fever syndromes
The purpose of this study is to determine the prevalence, clinical and genetic background of periodic fever syndromes, particularly familial Mediterranean fever (FMF), in central and south-eastern European countries. In this region a small number of FMF patients’ has been reported so far and carrier state is not known. Moreover, it is suspected that environmental influences can modify clinical picture.
Significance for science
Our research proposal was focused on systemic immune-mediated diseases which are one of the most common chronic disorders in pediatric population. Our studies were clinically focused with two main objectives including development of better diagnostic ability for early identification of patients with different systemic immune-mediated diseases and recognition of patients with systemic-immune mediated disease that have worse long-term outcome and impact of treatment on the long-term outcome. Ad 1. The research project significantly contributed to characterization of clinical spectrum in children with antiphospholipid antibodies and provided an insight in the pathogenesis of antiphospholipid syndrome. In the field of childhood-onset systemic lupus erythematosus we were able to further characterize intracellular STAT1 and STAT5 T cell signaling pathways of cytokines, important for their homeostasis and function. The results of our studies point to possible new targets of more specific and less toxic therapy in SLE and APS with kinase inhibitors. Ad 2. The prospective, longitudinal study provided more reliable data on the safety and efficacy of influenza vaccination in healthy adults and in children with JIA and contributed evidence-based data to the scientific and public debate on the role of influenza vaccination. Ad 3. The research project provided original new data on the formation of anti-drug antibodies in pediatric patients with rheumatic diseases treated with biologic agents which was associated with altered pharmacokinetics of the biologics and correlated with therapeutic efficacy. We evaluated also genetic markers of methotrexate metabolism and assessed their value as predictors for efficacy and toxicity of treatment in children with juvenile idiopathic arthritis. Ad 4. In a collaborative study published in the journal Science we identified a novel form of primary immunodeficiency caused by gain-of-function mutation in the PIK3CD gene and associated with increased kinase activity of p110? protein. Moreover, we provided comprehensive data on demographic and clinical features in the largest published series of patients with autoinflammatory diseases. The research project provided also original data on the prevalence, clinical and genetic background of periodic fever syndromes, particularly familial Mediterranean fever in central and south-eastern European countries.
Significance for the country
The research proposal was clinically focused and was aimed to improvement of health care including development of new clinical and laboratory diagnostic protocols and more targeted treatment of systemic autoimmune diseases. The results of our research project have improved diagnostic process of pediatric patients with systemic-immune mediated dieases including earlier recognition during their disease course and implementation of early treatment that could improve long-term outcome. Details are presented in the item No. 9.
Most important scientific results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
