HUMORAL IMMUNITY AGAINST VIRAL ANTIGENS IN TYPE 1 DIABETES: ALTERED IgA-CLASS IMMUNE RESPONSE AGAINST COXSACKIE B4 VIRUS

Abstract Aims/hypothesis Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and immune response actions on immunity and the gut microbiome. Methods A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6 months to 2.99 years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. Results Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. Conclusions/interpretation The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. Trial registration Clinicaltrials.gov NCT02547519 Funding The main funding source was the German Center for Diabetes Research (DZD e.V.) Graphical abstract

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Impaired Primary Immune Response in Type-1 Diabetes: Results from a Controlled Vaccination Study

Clinical Immunology ◽

10.1006/clim.2002.5220 ◽

2002 ◽

Vol 103 (3) ◽

pp. 249-259 ◽

Cited By ~ 74

Author(s):

Nicole Eibl ◽

Martin Spatz ◽

Gottfried F. Fischer ◽

Wolfgang R. Mayr ◽

Aysen Samstag ◽

...

Keyword(s):

Immune Response ◽

Type 1 Diabetes ◽

Primary Immune Response

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Endocrine autoimmunity

Oxford Textbook of Endocrinology and Diabetes ◽

10.1093/med/9780199235292.003.1031 ◽

2011 ◽

pp. 34-44 ◽

Cited By ~ 2

Author(s):

Matthew J. Simmonds ◽

Stephen C. L. Gough

Keyword(s):

Immune Response ◽

Type 1 Diabetes ◽

Immune System ◽

Endocrine System ◽

Graves Disease ◽

Self Tolerance ◽

Autoimmune Attack ◽

Endocrine Organs

Dysfunction within the endocrine system can lead to a variety of diseases with autoimmune attack against individual components being some of the most common. Endocrine autoimmunity encompasses a spectrum of disorders including, e.g., common disorders such as type 1 diabetes, Graves’ disease, Hashimoto’s thyroiditis, and rarer disorders including Addison’s disease and the autoimmune polyendocrine syndromes type 1 (APS 1) and type 2 (APS 2) (see Table 1.6.1). Autoimmune attack within each of these diseases although aimed at different endocrine organs is caused by a breakdown in the immune system’s ability to distinguish between self and nonself antigens, leading to an immune response targeted at self tissues. Investigating the mechanisms behind this breakdown is vital to understand what has gone wrong and to determine the pathways against which therapeutics can be targeted. Before discussing how self-tolerance fails, we first have to understand how the immune system achieves self-tolerance.

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Four-year clinical remission of type 1 diabetes mellitus in two patients treated with sitagliptin and vitamin D3

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-16-0099 ◽

2016 ◽

Vol 2016 ◽

Cited By ~ 2

Author(s):

Marcelo Maia Pinheiro ◽

Felipe Moura Maia Pinheiro ◽

Margareth Afonso Torres

Keyword(s):

Diabetes Mellitus ◽

Immune Response ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Vitamin D3 ◽

Clinical Remission ◽

Insulin Production ◽

C Peptide ◽

New Onset

Summary Type 1 diabetes mellitus (T1DM) is a chronic disease characterized by autoimmune destruction of pancreatic beta cells and inadequate insulin production. Remission criteria in T1DM take into account serum levels of C-peptide and glycosylated hemoglobin, as well as the dose of insulin administered to the patient. However, remission of T1DM lasting longer than 1 year is rare. We describe here the cases of two young women who presented with positive glutamic acid decarboxylase (GAD) antibody and classic clinical manifestations of T1DM. Both patients had a prior history of Hashimoto’s thyroiditis. They were initially treated with a basal-bolus regimen of insulin (glargine and lispro/glulisine). Once their blood glucose levels were controlled, they were started on oral sitagliptin 100 mg and vitamin D3 5000 IU daily. After this therapy, both patients achieved clinical diabetes remission for 4 years, along with a decrease in anti-GAD antibody levels. These benefits were probably associated with immunological effects of these medications. Inhibition of dipeptidyl peptidase 4 (DPP-4) in animal models deregulates Th1 immune response, increases secretion of Th2 cytokines, activates CD4+CD25+FoxP3+ regulatory T-cells and prevents IL-17 production. Vitamin D3 also activates CD4+CD25+FoxP3+ regulatory T-cells, and these medications combined can improve the immune response in patients with new-onset T1DM and probably promote sustained clinical remission. Learning points: The use of sitagliptin and vitamin D3 in patients with new-onset type 1 diabetes mellitus (T1DM) may help decrease the daily insulin requirement by delaying beta cell loss and improving endogenous insulin production. The use of sitagliptin and vitamin D3 in new-onset T1DM could help regulate the imbalance between Th17 and Treg cells. Age 14 years or above, absence of ketoacidosis and positive C-peptide levels in patients with T1DM are good criteria to predict prolonged T1DM remission. The determination of anti-GAD antibodies and C-peptide levels could be helpful in the follow-up of patients in use of sitagliptin and vitamin D3, which could be associated with prolonged T1DM clinical remission.

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Development of a Bioconjugate Platform for Modifying the Immune Response of Autoreactive Cytotoxic T Lymphocytes Involved in Type 1 Diabetes

Bioconjugate Chemistry ◽

10.1021/acs.bioconjchem.9b00332 ◽

2019 ◽

Vol 30 (7) ◽

pp. 2049-2059 ◽

Cited By ~ 2

Author(s):

Neha Nandedkar-Kulkarni ◽

Abhishek R. Vartak ◽

Steven J. Sucheck ◽

Katherine A. Wall ◽

Anthony Quinn ◽

...

Keyword(s):

Immune Response ◽

Type 1 Diabetes ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes

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Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes

Acta Endocrinologica ◽

10.1530/eje.1.02271 ◽

2006 ◽

Vol 155 (4) ◽

pp. 633-642 ◽

Cited By ~ 14

Author(s):

Matti S Ronkainen ◽

Sanna Hoppu ◽

Sari Korhonen ◽

Satu Simell ◽

Riitta Veijola ◽

...

Keyword(s):

Type 1 Diabetes ◽

Young Children ◽

Genetic Susceptibility ◽

Humoral Immunity ◽

Disease Process ◽

Igg Subclasses ◽

Acid Decarboxylase ◽

Igg Subclass ◽

Increased Risk

Objective: The pattern of the humoral immunity to disease-associated autoantigens may reflect the severity of the autoimmune disease process. The purpose of this study was to delineate the maturation of the humoral immunity to one of the main autoantigens in type 1 diabetes (T1D), glutamic acid decarboxylase (GAD65). Design and methods: Serum samples were obtained for the detection of epitope- and isotype-specific antibodies sequentially with short intervals from 36 young children with HLA-conferred genetic susceptibility to T1D starting from the first appearance of GAD65Ab. During prospective observation, ten children developed T1D. Antibodies were analyzed using biotinylated anti-human immunoglobulin (Ig) antibodies and chimeric GAD molecules in radio-binding assays. Results: The immune response to GAD65 started as reactivity to the middle region and spread rapidly to the C-terminal region. IgG1 antibodies dominated among the isotypes from the first appearance of GAD65Ab, while other IgG subclasses were observed to a lesser extent. IgG4 antibodies emerged clearly as the last IgG subclass. A broad initial response comprising three to four IgG subclasses and the lack of an emerging IgG4 response during follow-up was associated with increased risk for progression to clinical diabetes (P<0.05). Conclusions: The humoral response to GAD65 epitope clusters is relatively uniform in young children, whereas there is conspicuous individual variation in IgG subclass responses except for IgG1. A narrow initial IgG subclass response to GAD65 and the emergence of IgG4 antibodies were characteristic of those who remained non-diabetic over the first few years of GAD65 autoimmunity.

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The Serum IL-6 Profile and Treg/Th17 Peripheral Cell Populations in Patients with Type 1 Diabetes

Mediators of Inflammation ◽

10.1155/2013/205284 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 25

Author(s):

Monika Ryba-Stanisławowska ◽

Maria Skrzypkowska ◽

Jolanta Myśliwska ◽

Małgorzata Myśliwiec

Keyword(s):

Immune Response ◽

Type 1 Diabetes ◽

Quantitative Analysis ◽

Inflammatory Diseases ◽

T Cell Subsets ◽

Cell Populations ◽

Peripheral Cell ◽

Chronic Inflammatory Diseases ◽

Cell Balance

IL-6 is a pleiotropic cytokine involved in the regulation of the immune response, inflammation, and hematopoeisis. Its elevated levels are found in a range of autoimmune and chronic inflammatory diseases. IL-6 is also involved in regulation of the balance between two T cell subsets: Tregs and Th17, which have contradictory functions in the control of inflammation. The present study provides a quantitative analysis regarding the Th17/Treg cell balance in peripheral blood of children with type 1 diabetes and its association with serum IL-6 level.

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