| 51. |
- Axelsson, Stina, 1981-
(författare)
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GAD65 An Immunomodulator in Type 1 Diabetes
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) is caused by a deficiency of insulin as a result of an autoimmune destruction of the pancreatic ² -cells. A possibility to preserve remaining ² -cells in children with newly diagnosed T1D is of great importance since sustained ² -cell function is recognized to result in reduced end-organ complications. Glutamic acid decarboxylase 65 (GAD65) is one of the major antigens targeted by self-reactive T cells in T1D, and immunomodulation with GAD65 formulated in aluminum (GAD-alum) has been considered both in prevention and treatment of T1D. Results from a Phase II trial have shown clinical effect of subcutaneous injections with GAD-alum, this was unfortunately not fully confirmed in the following larger Phase III trial which therefore was closed after 15 months. The general aim of this thesis was to study the immunomodulatory effect of GAD-alum-treatment in children with T1D participating in the Phase II and Phase III trials. We hypothesized that treatment with GAD-alum contributes to the preservation of residual insulin secretion through deviation of the GAD65-specific immune response from a destructive to a protective process, accompanied by a shift from T helper (Th) 1 towards a predominant Th2 profile. In the Phase II trial, GAD-alum-treated patients responded with an early GAD65-specific Th2 skewed cytokine secretion, with highest IL-5 and IL-13 secretion in clinical responders. Also, the CCR4/CCR5 ratio indicating balance between Th2/Tc2 and Th1/Tc1 responses, increased in treated patients. The recall response to GAD65 was characterized by a wide range of cytokines, but the relative contribution of each cytokine suggests a shift towards a more pronounced Th2-associated profile over time. Induction of a CD4+ cell subset upon GAD65-stimulation 4 years after treatment, suggesting clonal expansion of the memory T-cell compartment upon antigen re-challenge, was seen in parallel to a persistent GAD65-specific cytokine response. Finally, even if the phase III trial failed to reach the primary endpoint at 15 months, a subgroup analysis showed that the treatment had an effect on preservation of residual insulin secretion, but the effect was not seen until after 30 months. Taken together, these results suggest that GAD-alum treatment might exert its effect through induction of an early Th2 skewed immune response which tends to deviate away from a destructive Th1/Tc1 response upon GAD65 re-challenge, and generation of GAD65-specific memory T cells that produce cytokines and exert effector responses which may be important for regulating GAD65 immunity. Continued research to better understand how immunomodulation with autoantigen modifies T-cell responses and also which patients are suitable for treatment, is crucial for optimizing future intervention trials using ² -cell antigens.
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| 52. |
- Axelsson, Stina, et al.
(författare)
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Long-Lasting Immune Responses 4 Years after GAD-Alum Treatment in Children with Type 1 Diabetes
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- A phase II clinical trial with glutamic acid decarboxylase (GAD) 65 formulated with aluminium hydroxide (GAD-alum) has shown efficacy in preserving residual insulin secretion in children and adolescents with recent-onset type 1 diabetes (T1D). We have performed a 4-year follow-up study of 59 of the original 70 patients to investigate long-term cellular and humoral immune responses after GAD-alum-treatment. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with GAD(65). Frequencies of naive, central and effector memory CD4+ and CD8+ T cells were measured, together with cytokine secretion, proliferation, gene expression and serum GAD(65) autoantibody (GADA) levels. We here show that GAD-alum-treated patients display increased memory T-cell frequencies and prompt T-cell activation upon in vitro stimulation with GAD(65), but not with control antigens, compared with placebo subjects. GAD(65)-induced T-cell activation was accompanied by secretion of T helper (Th) 1, Th2 and T regulatory cytokines and by induction of T-cell inhibitory pathways. Moreover, post-treatment serum GADA titres remained persistently increased in the GAD-alum arm, but did not inhibit GAD(65) enzymatic activity. In conclusion, memory T- and B-cell responses persist 4 years after GAD-alum-treatment. In parallel to a GAD(65)-induced T-cell activation, our results show induction of T-cell inhibitory pathways important for regulating the GAD(65) immunity.
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| 53. |
- Axelsson, Stina, et al.
(författare)
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Preserved C-peptide 30 months after GAD-alum treatment of children and adolescents with recent-onset type 1 diabetes, and its relation to immune markers
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Glutamic acid decarboxylase 65 kDa isoform (GAD65) is a major autoantigen in type 1 diabetes (T1D). Although alum-formulated GAD65 (GAD-alum) induced preservation of residual insulin secretion in a previous clinical Phase II trial, recent Phase II and Phase III trials failed to reach their primary end-points. The European Phase III trial was therefore closed after 15 months, and the 30 months follow-up period was completed only for a minority of the patients. This study aimed to assess whether GAD-alum preserved β-cell function in those recent-onset T1D patients who completed their 30 months visit in the European Phase III trial, and to characterize their GAD65-induced cytokine secretion and proliferation. Peripheral blood mononuclear cells (PBMC) were isolated at baseline and after 1, 3, 9, 15 and 21 months from the 148 Swedish subjects included in the Phase III GAD-alum trial, and also at 30 months from 45 patients who had reached the final visit before the trial was closed. Patients had been randomly assigned into three arms: 4 doses of GAD-alum (4D), 2 doses of GAD-alum followed by two doses of placebo (2D), or 4 doses of placebo. Cytokine secretion was detected in cell culture supernatants by Luminex, after 7 days of in vitro culture. Cell proliferation was determined by 3H thymidine incorporation assay. Fasting and stimulated C-peptide was analysed in serum. Patients treated with 2 doses of GAD-alum had less decline of both fasting (p=0.040) and stimulated C-peptide (p=0.012) after 30 months, and a larger proportion of these patients preserved >25% of their initial stimulated C-peptide AUC compared to placebo (p=0.012). Both 2D and 4D patients showed increased PBMC proliferation to GAD65 and a cytokine profile that tended to switch towards a more predominant Th2 associated profile over time. The results support the concept of GAD-alum treatment, but no specific immune markers have been identified.
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| 54. |
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| 55. |
- Aydemir, O, et al.
(författare)
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Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes
- 2019
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 68:7, s. 1523-1527
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D) involves the interaction of multiple gene variants, environmental factors, and immunoregulatory dysfunction. Major T1D genetic risk loci encode HLA-DR and -DQ. Genetic heterogeneity and linkage disequilibrium in the highly polymorphic HLA region confound attempts to identify additional T1D susceptibility loci. To minimize HLA heterogeneity, T1D patients (N = 365) and control subjects (N = 668) homozygous for the HLA-DR3 high-risk haplotype were selected from multiple large T1D studies and examined to identify new T1D susceptibility loci using molecular inversion probe sequencing technology. We report that risk for T1D in HLA-DR3 homozygotes is increased significantly by a previously unreported haplotype of three single nucleotide polymorphisms (SNPs) within the first intron of HLA-DRA1. The homozygous risk haplotype has an odds ratio of 4.65 relative to the protective homozygous haplotype in our sample. Individually, these SNPs reportedly function as “expression quantitative trait loci,” modulating HLA-DR and -DQ expression. From our analysis of available data, we conclude that the tri-SNP haplotype within HLA-DRA1 may modulate class II expression, suggesting that increased T1D risk could be attributable to regulated expression of class II genes. These findings could help clarify the role of HLA in T1D susceptibility and improve diabetes risk assessment, particularly in high-risk HLA-DR3 homozygous individuals.
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| 56. |
- Bagavathy Shanmugam, Karthikeyan, et al.
(författare)
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Prenatal exposure to environmental contaminants and cord serum metabolite profiles in future immune-mediated diseases
- 2024
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Ingår i: Journal of Exposure Science and Environmental Epidemiology. - : Nature Publishing Group. - 1559-0631 .- 1559-064X. ; 34:4, s. 647-658
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prenatal exposure to environmental contaminants is a significant health concern because it has the potential to interfere with host metabolism, leading to adverse health effects in early childhood and later in life. Growing evidence suggests that genetic and environmental factors, as well as their interactions, play a significant role in the development of autoimmune diseases.OBJECTIVE: In this study, we hypothesized that prenatal exposure to environmental contaminants impacts cord serum metabolome and contributes to the development of autoimmune diseases.METHODS: We selected cord serum samples from All Babies in Southeast Sweden (ABIS) general population cohort, from infants who later developed one or more autoimmune-mediated and inflammatory diseases: celiac disease (CD), Crohn's disease (IBD), hypothyroidism (HT), juvenile idiopathic arthritis (JIA), and type 1 diabetes (T1D) (all cases, N = 62), along with matched controls (N = 268). Using integrated exposomics and metabolomics mass spectrometry (MS) based platforms, we determined the levels of environmental contaminants and metabolites.RESULTS: Differences in exposure levels were found between the controls and those who later developed various diseases. High contaminant exposure levels were associated with changes in metabolome, including amino acids and free fatty acids. Specifically, we identified marked associations between metabolite profiles and exposure levels of deoxynivalenol (DON), bisphenol S (BPS), and specific per- and polyfluorinated substances (PFAS).IMPACT STATEMENT: Abnormal metabolism is a common feature preceding several autoimmune and inflammatory diseases. However, few studies compared common and specific metabolic patterns preceding these diseases. Here we hypothesized that exposure to environmental contaminants impacts cord serum metabolome, which may contribute to the development of autoimmune diseases. We found differences in exposure levels between the controls and those who later developed various diseases, and importantly, on the metabolic changes associated with the exposures. High contaminant exposure levels were associated with specific changes in metabolome. Our study suggests that prenatal exposure to specific environmental contaminants alters the cord serum metabolomes, which, in turn, might increase the risk of various immune-mediated diseases.
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| 57. |
- Baldimtsi, Evangelia, 1981-, et al.
(författare)
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HbA1c and the risk of developing peripheral neuropathy in childhood-onset type 1 diabetes : A follow-up study over 3 decades
- 2024
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Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 40:5
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: We have evaluated long-term weighted mean HbA1c (wHbA1c), HbA1c variability, diabetes duration, and lipid profiles in relation to the development of diabetic peripheral neuropathy (DPN), nephropathy, and retinopathy in childhood-onset type 1 diabetes.MATERIALS AND METHODS: In a longitudinal cohort study, 49 patients (21 women) with childhood-onset type 1 diabetes were investigated with neurophysiological measurements, blood tests, and clinical examinations after a diabetes duration of 7.7 (±3.3) years (baseline) and followed with repeated examinations for 30.6 (±5.2) years. We calculated wHbA1c by integrating the area under all HbA1c values since the diabetes diagnosis. Lipid profiles were analysed in relation to the presence of DPN. Long-term fluctuations of HbA1c variability were computed as the standard deviation of all HbA1c measurements. Data regarding the presence of other diabetes complications were retrieved from medical records.RESULTS: In this follow-up study, 51% (25/49) of the patients fulfilled electrophysiological criteria for DPN. In nerve conduction studies, there was a deterioration in the amplitudes and conduction velocities for the median, peroneal, and sural nerves over time. Patients with DPN had a longer duration of diabetes, higher wHbA1c, and increased HbA1c variability. The lowest wHbA1c value associated with the development of DPN was 62 mmol/mol (7.8%). The presence of albuminuria and retinopathy was positively correlated with the presence of neuropathy.CONCLUSIONS: More than half of the patients had developed DPN after 30 years. None of the patients who developed DPN had a wHbA1c of less than 62 mmol/mol (7.8%).
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| 58. |
- Baldimtsi, Evangelia, 1981-
(författare)
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Studies on risk factors for long-term development of peripheral neuropathy in Type 1 Diabetes Patients
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetic peripheral neuropathy (DPN) is a highly prevalent microvascular complication of both type 1 and type 2 diabetes. As many as 30% of individuals with type 1 diabetes and 50% of patients with type 2 diabetes develop DPN after 25 and 10 years of disease, respectively. Type 1 diabetes often develops in younger ages of life. This means that when DPN occurs, the individuals with type 1 diabetes are still at a relatively young age. On the contrary, type 2 diabetes, with an even higher prevalence of DPN, mainly affects older people already having other risk factors and an age-related decline in nerve functions.Despite advancements in glucose control, the treatment with new insulin analogues, the introduction of insulin pumps, or the extended use of glucose sensors, the risk of this diabetes complication is not significantly declining. DPN is still a leading cause of non-traumatic limb amputation and significantly increases cardiovascular and all-cause mortality. Based on previous studies, it is suggested that there is a cluster of factors, including long-term metabolic control, obesity, hypertension, dyslipidemia, and especially high triglyceride levels, which impact the onset and progression of neuropathy. Moreover, recent studies have highlighted that low-grade inflammation plays an important role in the pathogenesis of DPN by leading to a cascade of events, including altered function of chemokines and imbalances in atherosclerotic plaque stability and platelet function. Overall, there is a great need to better understand the pathogenesis of DPN and the underlying risk factors for manifest disease to develop new preventive and curative strategies for patients with diabetes.This thesis aimed to examine the cumulative incidence and prevalence of diabetic neuropathy, the natural course of neurophysiological changes, and novel biomarkers associated with DPN among patients with childhood-onset type 1 diabetes longitudinally followed for 30 years. This study was an observational, longitudinal follow-up study, and the primary data were collected prospectively.More specifically, we investigated the role of circulating inflammatory factors, chemokines, and metalloproteinases in the risk of developing DPN. We also examined the impact of longterm metabolic control on the prevalence of DPN over a 30-year follow-up period in this cohort.In Paper I, we explored the occurrence of biomarkers of ongoing inflammatory processes, particularly chemokines, in DPN through a cross-sectional analysis. Chemokines are a subgroup of cytokines that regulate various immune system reactions. They contribute to increased inflammatory systematic response, leading to increased co-morbidity. Our main hypothesis was that patients with type 1 diabetes and concomitant DPN would exhibit increased circulating chemokines levels compared to control subjects and patients without DPN. The main result of this analysis was the detection of higher levels of the CXCL9 chemokine in patients with type 1 diabetes and DPN in comparison to healthy control subjects. Furthermore, CXCL8 and CXCL10 chemokines were correlated with impaired nerve function in all patients with diabetes.In Paper II, we examined the association between markers for atherosclerotic plaque stability, inflammation, and platelet function and the prevalence of diabetic neuropathy and nephropathy. The main biomarkers analyzed were Matrix Metalloproteinase-9 (MMP-9) and its tissue inhibitor TIMP-1, soluble P-selectin (sP-selectin), and Neutrophil Gelatinaseassociated Lipocalin-2 (NGAL).Our findings revealed that TIMP-1 and high-sensitive CRP levels were increased in patients with DPN compared to controls and patients without DPN. sP-selectin levels were elevated in the patients with DPN compared with healthy controls. TIMP-1, NGAL, and MMP-9 were associated with diabetic nephropathy and albuminuria. Our findings indicate that circulating biomarkers might be involved in microvascular complications.In Paper III, we comprehensively examined the importance of long-term metabolic control for the progression of DPN in patients with type 1 diabetes followed for 30 years. In a longitudinal cohort study, 49 patients with type 1 diabetes diagnosed in childhood were investigated with nerve conduction tests. Weighted HbA1c (wHbA1c) and HbA1c variability were calculated after a diabetes duration of up to 30.6 (±5.2) years.A high DPN prevalence of 51% was found using nerve conduction tests after a median diabetes duration of 30 years. Deterioration in the amplitudes of both sural and peroneal nerves was found. Moreover, in the repeated nerve conduction tests (NCS), amplitudes showed a gradual deterioration more consistently than velocities, suggesting that measurements of amplitudes are particularly useful in evaluating nerve conduction changes in DPN.No patient developed neuropathy while preserving a weighted mean HbA1c of less than 62 mmol/mol (7.8%). Corresponding wHbA1c for avoiding nephropathy were wHbA1c < 68 mmol/mol (8.4 %) and for severe retinopathy < 56 mmol/mol (7.3%).Risk factors in our study associated with DPN included long diabetes duration and impaired glycemic control with higher wHbA1c and significant variability of HbA1c over time, high triglyceride levels, and low HDL-cholesterol levels.In summary, the findings of this thesis highlight the importance of maintaining stable glycemic control and treating traditional cardiovascular covariates such as dyslipidemia in order to reduce DPN. The results also indicate that patients with type 1 diabetes and concomitant diabetes neuropathy display higher levels of chemokines and metalloproteinases, supporting the hypothesis that atherosclerosis and low-grade inflammation may contribute to the pathogenesis of diabetic neuropathy.
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| 59. |
- Barcenilla, Hugo, et al.
(författare)
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Intralymphatic GAD-alum Injection Modulates B Cell Response and Induces Follicular Helper T Cells and PD-1+ CD8+ T Cells in Patients With Recent-Onset Type 1 Diabetes
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naïve and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD65 only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes.
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| 60. |
- Barcenilla, Hugo, et al.
(författare)
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Mass Cytometry Identifies Distinct Subsets of Regulatory T Cells and Natural Killer Cells Associated With High Risk for Type 1 Diabetes
- 2019
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin producing beta-cells. The time from onset of islet autoimmunity to manifest clinical disease can vary widely in length, and it is fairly uncharacterized both clinically and immunologically. In the current study, peripheral blood mononuclear cells from autoantibody-positive children with high risk for T1D, and from age-matched healthy individuals, were analyzed by mass cytometry using a panel of 32 antibodies. Surface markers were chosen to identify multiple cell types including T, B, NK, monocytes, and DC, and antibodies specific for identification of differentiation, activation and functional markers were also included in the panel. By applying dimensional reduction and computational unsupervised clustering approaches, we delineated in an unbiased fashion 132 phenotypically distinct subsets within the major immune cell populations. We were able to identify an effector memory Treg subset expressing HLA-DR, CCR4, CCR6, CXCR3, and GATA3 that was increased in the high-risk group. In addition, two subsets of NK cells defined by CD16(+) CD8(+) CXCR3(+) and CD16(+) CD8(+) CXCR3(+) CD11c(+) were also higher in the same subjects. High-risk individuals did not show impaired glucose tolerance at the time of sampling, suggesting that the changes observed were not the result of metabolic imbalance, and might be potential biomarkers predictive of T1D.
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