BeAT1D: Benign Autoimmunity and Type 1 Diabetes

Study Overview
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Brief Summary
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National multi-center non-interventional case-control cohort study with collection of biological samples to characterize the autoimmune T and B lymphocytes involved in the development of type 1 diabetes.

Detailed Description
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The overall objective of this study is to define the differential characteristics of autoimmune T and B lymphocytes across individuals with T1D, other forms of diabetes or autoimmunity, and no disease. The hypothesis is that the characterization of the autoimmune T and B lymphocytes involved in T1D development may allow us to clarify the pathophysiological mechanisms of disease and to identify novel biomarkers for diagnostic, prognostic and therapeutic follow-up applications.

Official Title
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BeAT1D: Benign Autoimmunity and Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Other: Biosampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes: type 1 diabetes, as defined by hyperglycemia and long-term insulin therapy started within 6 months from clinical onset; and/or the presence of at least one anti-islet auto-antibody. Other forms of diabetes or autoimmune endocrinopathy: other forms of diabetes (e.g. type 2, ketosis-prone, familial, secondary, immunotherapy-induced diabetes); and/or other autoimmune endocrinopathies, isolated or multiple. No diabetes: absence of diabetes or impaired glucose tolerance; absence of tumor, infectious or immune pathologies, or other conditions related to autoimmune or metabolic alterations that may bias the variables under study. Lymphadenectomy planned in the frame of an abdominal surgery: pancreatic lymphadenectomy planned at the occasion of an abdominal surgery for the treatment of an underlying condition. Exclusion Criteria: For all participants: ongoing pregnancy; known HIV/HCV infection; absence of social security coverage; placement under judicial protection; absence of signature of the informed study consent.

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Type 1 diabetes<br>As defined by the presence of hyperglycemia and/or islet auto-antibodies. | Other: Biosampling<br>* Collection of blood and stool specimens; and collection of lymph node specimens for the group undergoing surgical lymphadenectomy.<br>|
| Other forms of diabetes or autoimmune endocrinopathy<br>Type 2 diabetes, ketosis-prone diabetes, familial diabetes, secondary diabetes, immunotherapy-induced diabetes; and/or autoimmune endocrinopathies. | Other: Biosampling<br>* Collection of blood and stool specimens; and collection of lymph node specimens for the group undergoing surgical lymphadenectomy.<br>|
| No diabetes<br>No diabetes or impaired glucose tolerance; no cancer, infectious or immune pathologies; no other condition related to autoimmune and metabolic alterations that may bias the variables under study. | Other: Biosampling<br>* Collection of blood and stool specimens; and collection of lymph node specimens for the group undergoing surgical lymphadenectomy.<br>|
| Lymphadenectomy planned at the occasion of an abdominal surgery<br>Patients undergoing a lymphadenectomy during surgery for the treatment of their underlying pathology. | Other: Biosampling<br>* Collection of blood and stool specimens; and collection of lymph node specimens for the group undergoing surgical lymphadenectomy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define the frequency and phenotype of autoimmune T lymphocytes reactive to islet antigens in the different study groups. | As measured by flow cytometry and sequencing techniques, with a sample size sufficient to attain a 92% statistical power and 5% alpha risk. Frequency will be expressed as number of antigen-reactive T lymphocytes per 100,000 total T lymphocytes (e.g. 20/100,000 or 0.02%). Phenotype will be expressed as percent of antigen-reactive T lymphocytes expressing a given phenotype, e.g. 20% naïve (CD45RA+CCR7+). These 2 measures will be aggregated by expressing the frequency of antigen-reactive T lymphocytes per 100,000 total T lymphocytes expressing a given phenotype, e.g. 20/100,000 antigen-reactive T lymphocytes with 20% naïve will be expressed as 4/100,000 naive antigen-reactive T lymphocytes. | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define the frequency and phenotype of autoimmune B lymphocytes reactive to islet antigens in the different study groups. | As measured by flow cytometry and sequencing techniques, with a sample size sufficient to attain a 92% statistical power and 5% alpha risk. Frequency will be expressed as number of antigen-reactive B lymphocytes per 100,000 total B lymphocytes (e.g. 20/100,000 or 0.02%). Phenotype will be expressed as percent of antigen-reactive B lymphocytes expressing a given phenotype, e.g. 20% memory (CD24+CD38-negative). These 2 measures will be aggregated by expressing the frequency of antigen-reactive B lymphocytes per 100,000 total B lymphocytes expressing a given phenotype, e.g. 20/100,000 antigen-reactive B lymphocytes with 20% memory will be expressed as 4/100,000 memory antigen-reactive B lymphocytes. | 6 years | 
| To identify novel islet epitopes recognized by autoimmune T and B lymphocytes. | As measured by a lymphocyte frequency within the expected range, e.g. 1-50/million. | 6 years | 
| To define the phenotype of these lymphocytes. | As defined by exploratory analyses based on omics techniques. | 6 years | 
| To define the pathogenicity of these lymphocytes against pancreatic beta cells. | As measured by an in vitro killing of beta-cell targets significantly (e.g. >2-fold) higher than the killing observed with control lymphocytes. | 6 years | 
| To define the antigen receptors used by these lymphocytes to recognize their target epitopes. | As defined by sequencing techniques and sequence annotation using IMGT and MiXCR. Sequence sharing and similarities across receptors will be measured using MiXCR and stringdist. | 6 years | 
| To define the correlation between the biomarkers analyzed and insulin secretion. | As measured based on the correlation with fasting C-peptide levels >0.2 nM. | 6 years | 
| To define the differences between lymphocytes in the blood and those in pancreatic lymph nodes. | As measured using the previous frequency and phenotype readouts. | 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autoimmunity, Lymphocytes, Type 1 diabetes, Beta cells, Biomarkers