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  • 1.
    Hjorth, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ryden, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Faresjo, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    GAD-alum treatment induces GAD(65)-specific CD4(+)CD25(high)FOXP3(+) cells in type 1 diabetic patients2011In: CLINICAL IMMUNOLOGY, ISSN 1521-6616, Vol. 138, no 1, p. 117-126Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes results from autoimmune destruction of insulin producing pancreatic beta-cells. We have shown that treatment with alum-formulated glutamic acid decarboxylase 65 (GAD-alum) preserved residual insulin secretion and induced antigen-specific responses in children with recent onset type 1 diabetes. The aim of this study was to further investigate the immunomodulatory effect of GAD-alum, focusing on CD4(+)CD25(high) cells and their association to cytokine secretion. Samples obtained 21 and 30 months after the initial injection of GAD-alum or placebo were included in the present study. GAD(65)-stimulation enhanced the percentage of CD4(+)CD25(high)FOXP3(+) cells, but reduced the percentage of CD4(+)CD25(+) cells, in samples from the GAD-alum treated group. Further, the GAD(65)-induced secretion of IL-5, -10, and -13 correlated with the expression of CD4(+)CD25(high)FOXP3(+) cells, but inversely with CD4(+)CD25(+) cells. These new data suggest that GAD-alum treatment induced GAD(65)-specific T cells with regulatory features.

  • 2. Order onlineBuy this publication >>
    Rydén, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Immune profile from high-risk to onset of Type 1 diabetes2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type 1 diabetes (T1D) is most often diagnosed early in life and is usually the result of an autoimmune attack on the insulin producing β-cells of the pancreas, leading to a lack of insulin secretion and life-long insulin treatment. The search for possible targets pin-pointing the β-cell destruction is a constant endeavour in the pursuit to prevent T1D onset. Hence, characterisation of the immunological profile and changes therein, during the pre-diabetic phase and disease course, is of outmost importance for the understanding of the immunological processes involved in T1D pathogenesis.

    The aim of this thesis was to investigate the immunological profile, focusing on markers associated with T helper (Th) cells, pro-inflammation and regulatory T cells (Treg), in individuals with a high risk of developing T1D, and in children with newly diagnosed T1D for up to two years post diagnosis. In addition, we wanted to efficiently expand Tregs and detect any difference in T cell number and composition among T1D, high-risk and healthy individuals.

    We found that high-risk individuals that later developed T1D had a lower mRNA expression of the regulatory associated markers forkhead box protein 3 (FOXP3), cytotoxic T lymphocyte associated antigen (CTLA)-4 and transforming growth factor (TGF)-β, following stimulation with the major autoantigen glutamic acid decarboxylase (GAD)65, in combination with higher secretions of the chemotactic pro-inflammatory cytokine machrophage inflammatory protein (MIP)-1β, in comparison with high-risk individuals remaining undiagnosed.

    In addition to a markedly altered immune profile during the pre-diabetic phase, T1D seems to present with an intense up-regulation of regulatory (FOXP3, TGF-β and CTLA-4) and pro-inflammatory (e.g. tumour necrosis factor-α) markers and a suppression of Th1 (e.g. interferon-γ) and Th2-associated immunity (e.g. interleukin-13). This up-regulation of regulatory markers, however, seems to occur too late in the immunological process to suppress the autoimmune attack directed against the pancreatic β-cells, and is probably reflecting the strong activation seen at onset of disease, rather than a cause of disease. Furthermore, we found low levels of circulating soluble CTLA-4 together with a positive correlation between soluble CTLA-4 protein secretion and mRNA expression in T1D, in parallel to a negative relation in healthy individuals. Moreover, low C-peptide was accompanied by low mitogen-induced soluble CTLA-4 protein, and vice versa, pointing to a link between clinical process, i.e. β-cell degradation and ability to secrete the regulatory molecule soluble CTLA-4 upon mitosis.

    Our study also suggests that T1D children in our cohort were associated with a lower percentage of CD4+CD25+CD127lo/-Tregs, however, the ones they had expanded well and even acquired a higher FOXP3 expression. We found an altered composition of CD4+ subsets, biased towards a higher CD4+CD25- ratio to Tregs.

    In conclusion, the pre-diabetic phase seems to be accompanied by lower mRNA expression of regulatory associated markers in combination with higher secretions of the chemotactic pro-inflammatory cytokine MIP-1β, acknowledging the importance of studying this period in order to characterise the origin of T1D development. In addition, T1D seems to present with an intense up-regulation of regulatory and pro-inflammatory markers and a suppression of Th1 and Th2-associated immunity followed by low levels of circulating soluble CTLA-4 and, suggestively, lower percentage of CD4+CD25+CD127lo/-Tregs. Whereas we found an altered composition of CD4+ subsets, biased towards a higher CD4+CD25- ratio to Tregs, the importance of said alteration remains to be shown.

    List of papers
    1. Switch from a dominant Th1-associated immune profile during the pre-diabetic phase in favour of a temporary increase of a Th3-associated and inflammatory immune profile at the onset of type 1 diabetes
    Open this publication in new window or tab >>Switch from a dominant Th1-associated immune profile during the pre-diabetic phase in favour of a temporary increase of a Th3-associated and inflammatory immune profile at the onset of type 1 diabetes
    2009 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 25, no 4, p. 335-343Article in journal (Refereed) Published
    Abstract [en]

    Background: Type 1 diabetes (T1D) is all autoimmune disease dominated by loss of self-tolerance resulting in depletion of the beta-cells. This Study aims to confirm previous observations of a dominant T-helper (Th)1-like profile during the period close to onset of disease. Further, to follow the immune response from onset to 2 years duration, the Study focused on spontaneous as well as autoantigen-induced immune profile.

    Methods: Peripheral blood mononuclear cells were collected 4 days and 1 and 2 years after diagnosis of T1D children, from healthy children carrying the human leukocyte antigen-risk genes and from high-risk children (ICA andgt;= 20 IJDF units). Peripheral blood mononuclear cells were stimulated with glutamic acid decarboxylase (GAD(65)) and phytohaemagglutinin (PHA). Cytokines and chemokines were detected in cell-culture supernatants by protein microarray (naive T-cells; interleukin (IL)-7, Th1; interferon-gamma, turnout necrosis factor-beta, Th2; IL-5, Th3; transforming growth factor-beta, T-regulatory cell type 1; IL-10 and inflammatory cytokines; tumour necrosis factor-alpha, IL-6 and chemokines; monocyte chemoattractant protein-1, monokine upregulated by IFN-gamma) in relation to clinical outcome (C-peptide).

    Results: High-risk children showed a dominant Th1-associated profile with high spontaneous and GAD(65)-induced secretion. The mitogen PHA instead induced a Th2-associated response exclusively in high-risk children. In contrast, newly diagnosed T1D children showed a pronounced Th3-associated cytokine profile as well as a burst of inflammatory cytokines and chemokines secreted both spontaneously and by GAD(65) and PHA stimulation. The immune response to GAD(65) and PHA, however, diminished with duration of disease.

    Conclusion: A dominant Thl-associated immune profile was observed during the pre-diabetic phase. This Th1 dominance, however, diminished in favour of a temporary increase in a Th3-associated and inflammatory immune profile at the onset of disease.

    Keywords
    Type 1 diabetes, high-risk children, T-helper cells, T-regulatory cells, cytokines, chemokines
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19142 (URN)10.1002/dmrr.958 (DOI)
    Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2017-12-13Bibliographically approved
    2. Altered immune profile from pre-diabetes to manifestation of type 1 diabetes
    Open this publication in new window or tab >>Altered immune profile from pre-diabetes to manifestation of type 1 diabetes
    2013 (English)In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 100, no 1, p. 74-84Article in journal (Refereed) Published
    Abstract [en]

    Background: While the mechanisms leading to beta-cell destruction and clinical onset of T1D are still unclear, the composition of the immune profile is probably important for the outcome of immune activity. The aim of this study was to investigate the composition and possible changes of the immunological profile, spontaneously and following stimulation with the autoantigens GAD(65), and HSP60, at high-risk and T1D onset and further to 8 months post diagnosis. Methods: Fifteen first-degree relatives of T1D patients with a high risk of developing the disease within five years, 25 children approximately four days and 8 months after diagnosis of T1D and 16 healthy children were included in the study. Cytokines (IL-1 beta, -6, -7, -10, -13, -17, IFN-gamma and TNF-alpha) and chemokines (CCL2, -3, -4, -5 and CXCL10) associated with Th1, Th2, Tr1 and inflammatory cells were detected in cell culture supernatants by Luminex-technique, and markers associated with regulatory T-cells (FOXP3, CTLA-4 and TGF-beta) by real-time RT-PCR. Results: High-risk individuals differed in immunity from that seen in healthy and T1D children. High-risk individuals had a low TNF-alpha response and fewer responders from mitogen exposure as well as low spontaneous secretions of IL-13 compared to healthy children. High-risk individuals that later developed T1D, had a lower FOXP3 and CTLA-4 mRNA expression, following stimulation with GAD(65), in combination with higher secretion of the pro-inflammatory chemokine CCL4. Conclusion: Changes in immunity seen in individuals with high risk of developing T1D points to alterations/actions in the immune system already early in the pre-diabetic phase.

    Keywords
    Type 1 diabetes, pre-diabetes, Th1, Th2, cytokines, chemokines
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-71941 (URN)10.1016/j.diabres.2013.01.014 (DOI)000317744300019 ()
    Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2017-12-08Bibliographically approved
    3. Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from Type 1 diabetic children
    Open this publication in new window or tab >>Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from Type 1 diabetic children
    Show others...
    2012 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 28, no 1, p. 84-96Article in journal (Refereed) Published
    Abstract [en]

    High levels of soluble cytotoxic T-lymphocyte antigen 4 (soluble CTLA-4), an alternative splice form of the regulatory T-cell (Treg) associated CTLA-4 gene, have been associated with type 1 diabetes (T1D) and other autoimmune diseases, such as Grave's disease and myasthenia gravis. At the same time, studies have shown soluble CTLA-4 to inhibit T-cell activation through B7 binding. This study aimed to investigate the role of soluble CTLA-4 in relation to full length CTLA-4 and other Treg associated markers in T1D children and in individuals with high or low risk of developing the disease.

    T1D children were studied at four days, one and two years after diagnosis in comparison to individuals with high or low risk of developing the disease. Isolated peripheral blood mononuclear cells (PBMC) were stimulated with the T1D-associated glutamic acid decarboxylase 65 (GAD65) and phytohaemagglutinin (PHA). Subsequently, soluble CTLA-4, full length CTLA-4, FOXP3 and TGF-β mRNA transcription were quantified and protein concentrations of soluble CTLA-4 were measured in culture supernatant and sera.

    Low protein concentrations of circulating soluble CTLA-4 and a positive correlation between soluble CTLA-4 mRNA and protein were seen in T1D, in parallel to a negative relation in healthy subjects. Further, low mitogen-induced soluble CTLA-4 was accompanied by low C-peptide, together indicating an inverse relation of soluble CTLA-4 between health and disease. Moreover, low mitogen-induced soluble CTLA-4 mRNA and low TGF-β mRNA expression were seen in high-risk individuals, indicating an alteration in activation and downregulating immune mechanisms already during the pre-diabetic phase.

    Place, publisher, year, edition, pages
    Wiley, 2012
    Keywords
    soluble CTLA-4; PBMC; Type 1 diabetes
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-71942 (URN)10.1002/dmrr.1286 (DOI)000298736800008 ()
    Note
    funding agencies|Swedish Child Diabetes Foundation (Barndiabetesfonden)||Schelin Foundation||Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2017-12-08Bibliographically approved
    4. Efficient expansion of cryopreserved CD4+CD25+CD127lo/- cells in Type 1 diabetes
    Open this publication in new window or tab >>Efficient expansion of cryopreserved CD4+CD25+CD127lo/- cells in Type 1 diabetes
    2011 (English)In: Results in Immunology, ISSN 2211-2839, Vol. 1, no 1, p. 36-44Article in journal (Refereed) Published
    Abstract [en]

    Increased attention has been drawn to the important role played by regulatory T-cells (Treg) in immune homoeostasis. However, the small numbers of Tregs make them elusive to study. We investigated the cryostability of Tregs and whether they can be expanded from cryopreserved peripheral blood mononuclear cells (PBMCs). Further, to elucidate if there is a difference in ex-vivo frequency or in vitro expansion of Tregs among T1D children (n=9), high-risk (n=7) and healthy (n=10) individuals, Tregs defined as CD4+CD25+CD127lo/− were isolated from cryopreserved PBMCs.

    Cryopreserved PBMCs maintained a stable expression of Treg-markers. Tregs were efficiently expanded in vitro from all donors and Tregs from T1D children acquired higher FOXP3 expression compared to healthy subjects. T1D children had a significantly lower percentage of Tregs among CD4+ T-cells and also lower Treg to CD4+CD25 cell ratios compared to healthy individuals.

    Place, publisher, year, edition, pages
    Elsevier, 2011
    Keywords
    Cryopreservation; Regulatory T-cells; Expansion; Type 1 diabetes
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-71943 (URN)10.1016/j.rinim.2011.08.001 (DOI)
    Available from: 2011-11-10 Created: 2011-11-10 Last updated: 2014-09-23Bibliographically approved
  • 3.
    Rydén, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Bolmeson, Caroline
    Cellular Autoimmunity Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Jonson, Carl-Oscar
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Cilio, Corrado M.
    Cellular Autoimmunity Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from Type 1 diabetic children2012In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 28, no 1, p. 84-96Article in journal (Refereed)
    Abstract [en]

    High levels of soluble cytotoxic T-lymphocyte antigen 4 (soluble CTLA-4), an alternative splice form of the regulatory T-cell (Treg) associated CTLA-4 gene, have been associated with type 1 diabetes (T1D) and other autoimmune diseases, such as Grave's disease and myasthenia gravis. At the same time, studies have shown soluble CTLA-4 to inhibit T-cell activation through B7 binding. This study aimed to investigate the role of soluble CTLA-4 in relation to full length CTLA-4 and other Treg associated markers in T1D children and in individuals with high or low risk of developing the disease.

    T1D children were studied at four days, one and two years after diagnosis in comparison to individuals with high or low risk of developing the disease. Isolated peripheral blood mononuclear cells (PBMC) were stimulated with the T1D-associated glutamic acid decarboxylase 65 (GAD65) and phytohaemagglutinin (PHA). Subsequently, soluble CTLA-4, full length CTLA-4, FOXP3 and TGF-β mRNA transcription were quantified and protein concentrations of soluble CTLA-4 were measured in culture supernatant and sera.

    Low protein concentrations of circulating soluble CTLA-4 and a positive correlation between soluble CTLA-4 mRNA and protein were seen in T1D, in parallel to a negative relation in healthy subjects. Further, low mitogen-induced soluble CTLA-4 was accompanied by low C-peptide, together indicating an inverse relation of soluble CTLA-4 between health and disease. Moreover, low mitogen-induced soluble CTLA-4 mRNA and low TGF-β mRNA expression were seen in high-risk individuals, indicating an alteration in activation and downregulating immune mechanisms already during the pre-diabetic phase.

  • 4.
    Rydén, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Altered immune profile from pre-diabetes to manifestation of type 1 diabetes2013In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 100, no 1, p. 74-84Article in journal (Refereed)
    Abstract [en]

    Background: While the mechanisms leading to beta-cell destruction and clinical onset of T1D are still unclear, the composition of the immune profile is probably important for the outcome of immune activity. The aim of this study was to investigate the composition and possible changes of the immunological profile, spontaneously and following stimulation with the autoantigens GAD(65), and HSP60, at high-risk and T1D onset and further to 8 months post diagnosis. Methods: Fifteen first-degree relatives of T1D patients with a high risk of developing the disease within five years, 25 children approximately four days and 8 months after diagnosis of T1D and 16 healthy children were included in the study. Cytokines (IL-1 beta, -6, -7, -10, -13, -17, IFN-gamma and TNF-alpha) and chemokines (CCL2, -3, -4, -5 and CXCL10) associated with Th1, Th2, Tr1 and inflammatory cells were detected in cell culture supernatants by Luminex-technique, and markers associated with regulatory T-cells (FOXP3, CTLA-4 and TGF-beta) by real-time RT-PCR. Results: High-risk individuals differed in immunity from that seen in healthy and T1D children. High-risk individuals had a low TNF-alpha response and fewer responders from mitogen exposure as well as low spontaneous secretions of IL-13 compared to healthy children. High-risk individuals that later developed T1D, had a lower FOXP3 and CTLA-4 mRNA expression, following stimulation with GAD(65), in combination with higher secretion of the pro-inflammatory chemokine CCL4. Conclusion: Changes in immunity seen in individuals with high risk of developing T1D points to alterations/actions in the immune system already early in the pre-diabetic phase.

  • 5.
    Rydén, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Efficient expansion of cryopreserved CD4+CD25+CD127lo/- cells in Type 1 diabetes2011In: Results in Immunology, ISSN 2211-2839, Vol. 1, no 1, p. 36-44Article in journal (Refereed)
    Abstract [en]

    Increased attention has been drawn to the important role played by regulatory T-cells (Treg) in immune homoeostasis. However, the small numbers of Tregs make them elusive to study. We investigated the cryostability of Tregs and whether they can be expanded from cryopreserved peripheral blood mononuclear cells (PBMCs). Further, to elucidate if there is a difference in ex-vivo frequency or in vitro expansion of Tregs among T1D children (n=9), high-risk (n=7) and healthy (n=10) individuals, Tregs defined as CD4+CD25+CD127lo/− were isolated from cryopreserved PBMCs.

    Cryopreserved PBMCs maintained a stable expression of Treg-markers. Tregs were efficiently expanded in vitro from all donors and Tregs from T1D children acquired higher FOXP3 expression compared to healthy subjects. T1D children had a significantly lower percentage of Tregs among CD4+ T-cells and also lower Treg to CD4+CD25 cell ratios compared to healthy individuals.

  • 6.
    Rydén, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Faresjo, Maria
    Jonköping University, Sweden Ryhov County Hospital, Sweden .
    General immune dampening is associated with disturbed metabolism at diagnosis of type 1 diabetes2014In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 75, no 1, p. 45-50Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Type 1 diabetes (T1D) is a serious diagnosis with the prospect of grave short- and long-term complications and even death if poorly managed. An attempt has been made to describe how clinical and immunological deviations might influence each other close to the diagnosis of T1D. METHODS: Sixty-nine newly diagnosed T1D children were studied together with a reference group of 30 healthy children. Cytokines (interleukin (IL)-6, IL-10, IL-13, IL-17, interferon-gamma, and tumor necrosis factor-alpha) were detected in in vitro culture by multiplex fluorochrome technique. Information of clinical status of the patients such as BMI, weight loss, pubertal stage, duration of symptoms, previous and/or ongoing infections, insulin requirement, and ketoacidosis were gathered together with the analysis of C-peptide and glycosylated hemoglobin (HbA1c). RESULTS: In general, low cytokine secretion was found at diagnosis of T1D. However, high C-peptide, short duration of symptoms, or an infection prior to diagnosis was associated with increased immune activity including proinflammatory, Th2-associated, and Tr1-associated cytokines. In contrast, ketoacidosis and later pubertal stage at onset of disease were more related to a Th1-prone response. CONCLUSION: There is a general immune dampening at diagnosis of T1D, which appears to be related to the metabolic state close to diagnosis.

  • 7.
    Rydén, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Stechova, Katerina
    Charles University Prague.
    Durilova, Marianna
    Charles University Prague.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Switch from a dominant Th1-associated immune profile during the pre-diabetic phase in favour of a temporary increase of a Th3-associated and inflammatory immune profile at the onset of type 1 diabetes2009In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 25, no 4, p. 335-343Article in journal (Refereed)
    Abstract [en]

    Background: Type 1 diabetes (T1D) is all autoimmune disease dominated by loss of self-tolerance resulting in depletion of the beta-cells. This Study aims to confirm previous observations of a dominant T-helper (Th)1-like profile during the period close to onset of disease. Further, to follow the immune response from onset to 2 years duration, the Study focused on spontaneous as well as autoantigen-induced immune profile.

    Methods: Peripheral blood mononuclear cells were collected 4 days and 1 and 2 years after diagnosis of T1D children, from healthy children carrying the human leukocyte antigen-risk genes and from high-risk children (ICA andgt;= 20 IJDF units). Peripheral blood mononuclear cells were stimulated with glutamic acid decarboxylase (GAD(65)) and phytohaemagglutinin (PHA). Cytokines and chemokines were detected in cell-culture supernatants by protein microarray (naive T-cells; interleukin (IL)-7, Th1; interferon-gamma, turnout necrosis factor-beta, Th2; IL-5, Th3; transforming growth factor-beta, T-regulatory cell type 1; IL-10 and inflammatory cytokines; tumour necrosis factor-alpha, IL-6 and chemokines; monocyte chemoattractant protein-1, monokine upregulated by IFN-gamma) in relation to clinical outcome (C-peptide).

    Results: High-risk children showed a dominant Th1-associated profile with high spontaneous and GAD(65)-induced secretion. The mitogen PHA instead induced a Th2-associated response exclusively in high-risk children. In contrast, newly diagnosed T1D children showed a pronounced Th3-associated cytokine profile as well as a burst of inflammatory cytokines and chemokines secreted both spontaneously and by GAD(65) and PHA stimulation. The immune response to GAD(65) and PHA, however, diminished with duration of disease.

    Conclusion: A dominant Thl-associated immune profile was observed during the pre-diabetic phase. This Th1 dominance, however, diminished in favour of a temporary increase in a Th3-associated and inflammatory immune profile at the onset of disease.

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