scholarly journals Immune outcomes and safety of high-dose oral insulin as a primary prevention immunotherapy in young autoantibody-negative children at high genetic risk for type 1 diabetes

2020 ◽  
Author(s):  
Robin Assfalg ◽  
Jan Knoop ◽  
Kristi L. Hoffman ◽  
Markus Pfirrmann ◽  
Jose Maria Zapardiel-Gonzalo ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune System ◽  
Primary Prevention ◽  
Genetic Risk ◽  
Adaptive Immune System ◽  
Oral Insulin ◽  
Dependent Manner ◽  
Cell Responses ◽  
Adaptive Immune

AbstractBackgroundOral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes with insulin autoimmunity often appearing in the first years of life. The aim of this study was to assess the safety and immunological effects of oral insulin immunotherapy as a primary prevention.MethodsA phase I/II randomized controlled trial (Clinicaltrials.govNCT02547519) was performed in 44 islet autoantibody-negative children aged 6 months to 2 years with familial and additional genetic risk for type 1 diabetes. Children were randomized 1:1 to daily insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months. Hypoglycemia was a major safety measure. The primary immune efficacy outcome was an induction of antibody or T cell responses to oral insulin.ResultsOral insulin was well tolerated with no changes in metabolic variables. The primary immune outcome did not differ between treatment groups and responses were observed in both children who received insulin (55%) or placebo (67%). Responses were, however, modified by the type 1 diabetes INSULIN gene. Among children with a susceptible genotype, antibody responses to insulin were more frequent in insulin-treated (cumulative response, 75.8%) as compared to placebo-treated children (18.2%; P = 0.0085). Mechanistic studies identified microbiome changes that were related to INSULIN genotype and frequent treatment-independent inflammatory episodes that modified the in vitro T cell responses to insulin in children with susceptible INSULIN genotypes.ConclusionThe study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe and engaged the adaptive immune system in an INSULIN genotype-dependent manner, and linked inflammatory episodes to the activation of insulin-responsive T cells.One Sentence SummaryOral insulin given daily to very young children was safe and may engage the adaptive immune system in an INSULIN genotype-dependent manner.

scholarly journals Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol

BMJ Open ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. e028578 ◽  
Author(s):  
Anette-Gabriele Ziegler ◽  
Peter Achenbach ◽  
Reinhard Berner ◽  
Kristina Casteels ◽  
Thomas Danne ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Primary Prevention ◽  
Beta Cell ◽  
Genetic Risk ◽  
Autoimmune Diabetes ◽  
Genetic Risk Score ◽  
Acid Decarboxylase ◽  
Oral Insulin ◽  
Double Blind

IntroductionThe POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes.Methods and analysisInfants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype. Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years. Treatment and follow-up is stopped if a child develops diabetes. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes. Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes.Ethics and disseminationThe study is approved by the ethical committees of all participating clinical sites. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial.Trial registration numberNCT03364868.

scholarly journals Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial

Diabetologia ◽  
2021 ◽  
Author(s):  
Robin Assfalg ◽  
Jan Knoop ◽  
Kristi L. Hoffman ◽  
Markus Pfirrmann ◽  
Jose Maria Zapardiel-Gonzalo ◽  
...  
Keyword(s):  
Immune Response ◽  
Type 1 Diabetes ◽  
Randomised Controlled Trial ◽  
Primary Outcome ◽  
Controlled Trial ◽  
Antibody Responses ◽  
Oral Insulin ◽  
Cell Responses ◽  
Randomised Controlled

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

scholarly journals Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials—GPPAD‐02 study design and first results

2019 ◽  
Vol 20 (6) ◽  
pp. 720-727 ◽  
Author(s):  
Christiane Winkler ◽  
Florian Haupt ◽  
Martin Heigermoser ◽  
Jose Zapardiel‐Gonzalo ◽  
Jasmin Ohli ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Primary Prevention ◽  
Study Design ◽  
Genetic Risk ◽  
First Results ◽  
Prevention Trials

scholarly journals LA RESPUESTA INMUNITARIA FRENTE AL VIRUS SARS-CoV-2

2020 ◽  
Vol 3 (9) ◽  
pp. 64-86
Author(s):  
SERGIO ROBERTO AGUILAR-RUIZ ◽  
FRANCISCO JAVIER SÁNCHEZ-PEÑA
Keyword(s):  
Immune System ◽  
Viral Entry ◽  
Immune Cells ◽  
Innate Immune System ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Adaptive Immune ◽  
Infected Cells ◽  
Systemic Pathology

The immune response against SARS-CoV-2 is similar to that against other viruses, where the innate immune system acts at early stages through the secretion of type 1 interferon (type 1 IFN), which prevents viral replication and the activation of natural killer (NK) cells. Later, the adaptive immune system acts through CD8+ cytotoxic T-lymphocytes and antibody production, which aim to destroy infected cells and block viral entry into cells. All the above leads to the elimination of the virus and mild symptomatology. However, in individuals with a weakened immune system, the viral infection spreads and leads to a potent inflammatory response, which leads to the recruitment of immune cells to the lungs, where they can cause severe pulmonary and even systemic pathology.

scholarly journals Neuroinflammation: An Integrating Overview of Reactive-Neuroimmune Cell Interactions in Health and Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Rodolfo Kölliker-Frers ◽  
Lucas Udovin ◽  
Matilde Otero-Losada ◽  
Tamara Kobiec ◽  
María Inés Herrera ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Immune System ◽  
Neurological Diseases ◽  
Adaptive Immune System ◽  
Brain Cell ◽  
Cns Inflammation ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Mediators Of Inflammation ◽  
Health And Disease

The concept of central nervous system (CNS) inflammation has evolved over the last decades. Neuroinflammation is the response of reactive CNS components to altered homeostasis, regardless of the cause to be endogenous or exogenous. Neurological diseases, whether traumatic, neoplastic, ischemic, metabolic, toxic, infectious, autoimmune, developmental, or degenerative, involve direct and indirect immune-related neuroinflammation. Brain infiltrates of the innate and adaptive immune system cells appear in response to an infective or otherwise noxious agent and produce inflammatory mediators. Mediators of inflammation include local and recruited cells and signals. Processes derived from extrinsic and intrinsic CNS diseases also elicit the CNS inflammatory response. A deeper understanding of immune-related inflammation in health and disease is necessary to find potential therapeutic targets for preventing or reducing CNS damage. This review is aimed at discussing the innate and adaptive immune system functions and their roles in regulating brain cell responses in disease and homeostasis maintenance.

scholarly journals Can we change autoimmunity in Type 1 Diabetes via insulin injection or oral insulin?

2019 ◽  
Vol 4 (1) ◽  
pp. e000196
Author(s):  
Muyun Cao
Keyword(s):  
Type 1 Diabetes ◽  
Immune System ◽  
Autoimmune Disease ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Early Stage ◽  
Insulin Injection ◽  
Oral Insulin

This article reviews recent immunotherapy studies of Type 1 Diabetes (T1D) which is an autoimmune disease. Researchers show that injecting human proinsulin peptides can safely modulate the immune system and affect beta-cell function in Type 1 Diabetes, but oral insulin consumption does not reduce the onset of Type 1 Diabetes in individuals at the early stage of the disease.

scholarly journals Islet-Resident Dendritic Cells and Macrophages in Type 1 Diabetes: In Search of Bigfoot’s Print

2021 ◽  
Vol 12 ◽  
Author(s):  
Henner Zirpel ◽  
Bart O. Roep
Keyword(s):  
Type 1 Diabetes ◽  
Dendritic Cells ◽  
Immune System ◽  
Current Knowledge ◽  
Treatment Options ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Future Research ◽  
Target Tissue

The classical view of type 1 diabetes assumes that the autoimmune mediated targeting of insulin producing ß-cells is caused by an error of the immune system. Malfunction and stress of beta cells added the target tissue at the center of action. The innate immune system, and in particular islet-resident cells of the myeloid lineage, could function as a link between stressed ß-cells and activation and recognition by the adaptive immune system. We survey the role of islet-resident macrophages and dendritic cells in healthy islet homeostasis and pathophysiology of T1D. Knowledge of islet-resident antigen presenting cells in rodents is substantial, but quite scarce in humans, in particular regarding dendritic cells. Differences in blood between healthy and diseased individuals were reported, but it remains elusive to what extend these contribute to T1D onset. Increasing our understanding of the interaction between ß-cells and innate immune cells may provide new insights into disease initiation and development that could ultimately point to future treatment options. Here we review current knowledge of islet-resident macrophages and dendritic cells, place these in context of current clinical trials, and guide future research.

Evolution and age characteristics of the innate and adaptive immune system

2016 ◽  
Vol 75 (3) ◽  
pp. 74-84 ◽  
Author(s):  
A.E. Abaturov ◽  
◽  
E.A. Agafonova ◽  
N.I. Abaturova ◽  
V.L. Babich ◽  
...  
Keyword(s):  
Immune System ◽  
Adaptive Immune System ◽  
Adaptive Immune

Genetic Risk for Type 1 Diabetes Profoundly Influences the Core Gut Microbiome in Children

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 209-LB ◽  
Author(s):  
JORDAN RUSSELL ◽  
LUIZ ROESCH ◽  
MARK A. ATKINSON ◽  
DESMOND SCHATZ ◽  
ERIC W. TRIPLETT ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiome ◽  
Genetic Risk ◽  
The Core
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