Characterization of Autoreactive Regulatory and Conventional CD4 T Cells in Recent Onset Type 1 Diabetes and Control Individuals
- Conditions
- Type 1 Diabetes
- Interventions
- Biological: Frequency of Treg and TeffsBiological: Phenotype of Treg and TeffsBiological: RNA seq analysisBiological: HLA typingBiological: beta-cell autoantibody dosageBiological: Glycated haemoglobin (HbA1C) dosageBiological: blood glucose dosageBiological: C-peptide dosage
- Registration Number
- NCT06427421
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
Type 1 diabetes (T1D) is caused by an autoimmune response leading to the destruction of pancreatic beta cells. The disease association with particular HLA class II alleles, particularly HLA-DQ8, indicates the implication of CD4 T cells in its aetiology. The hypothesis is therefore that T1D starts by the loss of tolerance in autoreactive CD4 T cells. This might result from alterations in conventional autoreactive CD4 T cells (Tcons), which drive disease, or autoreactive regulatory CD4 T cells expressing the transcription factor FOXP3 (Tregs), which normally maintain immune tolerance. The investigators expect that the characterization of HLA-DQ8-restricted Tcons and Tregs in recent onset HLA-DQ8+ T1D patients shall shed light on the molecular mechanisms underpinning T1D development. This knowledge will guide the development of novel cell therapies harnessing the power of genetically engineered Tregs expressing the relevant antigen receptor to restore immune homeostasis upon cell transfer. The ultimate goal is to reach a curative effect
- Detailed Description
During the development of type 1 diabetes (T1DM), regulatory T cells (Treg) are modified and their protective role is no longer optimal, particularly against pathology-specific autoreactive antigens. The hypothesis is that in patients with T1DM, the function and phenotype of Treg cells, as well as their receptor repertoire for the antigen to which they are specific (TCR), no longer allow them to control tolerance. The in-depth study of these cells, at both genetic and molecular levels, will enable a major breakthrough in our understanding of the pathophysiology of T1DM, and in the development of targeted cell therapy.
The investigators expect major/important differences between patient Tregs and those of the control population in this study, at the molecular, phenotypic and functional levels. These differences will highlight the TCRs recognizing the target self-antigens. In this way, investigators expect to be able to select a limited number of Treg TCRs that could ultimately be used in cell therapy to restore the protective role of Tregs in these patients.
Thus, this knowledge will enable to propose in the future a more effective immunotherapy with a long-term effect, in order to improve the management of patients with autoimmune diabetes and potentially cure them.
Accordingly, yhe investigators will study insulin-specific Tregs in T1DM patients and control individuals, as well as conventional T cells directed against the same antigen, which in patients are implicated in the disease. This will include a study of their functional status, their transcriptomic profile, as well as their TCRs and their fine recognition properties of the major diabetes self-antigen, insulin.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 80
Newly diagnosed T1DM group:
- Age ≥ 6 years and < 18 years on day of inclusion;
- Weight ≥ 12 kg;
- Newly diagnosed T1DM, diagnosis defined according to International Society of Pediatric and Adolescent Diabetes (ISPAD) criteria by: hyperglycemia > 2g/L and/or ketonemia and/or polyuro-polydipsia and/or weight loss ;
- Absence of other associated inflammatory or autoimmune diseases;
- Affiliation with a health insurance scheme or beneficiary (excluding AME);
- Written consent of parental guardians;
- Ability to understand and read French.
Control group :
- Age ≥ 6 years and < 18 years on the day of inclusion;
- Weight ≥ 12 kg;
- No personal history of T1DM;
- Affiliation with a health insurance scheme or entitled person (excluding AME);
- Written consent from parental guardians;
- Ability to understand and read French.
Newly diagnosed T1DM group:
- Use of corticosteroids in the month prior to blood sampling
- Contraindication to the use of anaesthetic cream for blood sampling.
Control group :
- History of autoimmune or inflammatory disease
- Use of corticosteroids in the month preceding blood sampling
- Contraindication to the use of anaesthetic cream for blood sampling
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control group RNA seq analysis children aged 6 to under 18 on the day of inclusion, with no history of type 1 diabetes Control group Phenotype of Treg and Teffs children aged 6 to under 18 on the day of inclusion, with no history of type 1 diabetes Newly diagnosed T1DM group beta-cell autoantibody dosage children aged 6 to under 18 on the day of inclusion, with a recent diagnosis of type 1 diabetes Control group beta-cell autoantibody dosage children aged 6 to under 18 on the day of inclusion, with no history of type 1 diabetes Control group blood glucose dosage children aged 6 to under 18 on the day of inclusion, with no history of type 1 diabetes Newly diagnosed T1DM group Phenotype of Treg and Teffs children aged 6 to under 18 on the day of inclusion, with a recent diagnosis of type 1 diabetes Control group Frequency of Treg and Teffs children aged 6 to under 18 on the day of inclusion, with no history of type 1 diabetes Newly diagnosed T1DM group Frequency of Treg and Teffs children aged 6 to under 18 on the day of inclusion, with a recent diagnosis of type 1 diabetes Newly diagnosed T1DM group HLA typing children aged 6 to under 18 on the day of inclusion, with a recent diagnosis of type 1 diabetes Control group HLA typing children aged 6 to under 18 on the day of inclusion, with no history of type 1 diabetes Control group Glycated haemoglobin (HbA1C) dosage children aged 6 to under 18 on the day of inclusion, with no history of type 1 diabetes Control group C-peptide dosage children aged 6 to under 18 on the day of inclusion, with no history of type 1 diabetes Newly diagnosed T1DM group RNA seq analysis children aged 6 to under 18 on the day of inclusion, with a recent diagnosis of type 1 diabetes
- Primary Outcome Measures
Name Time Method Frequency and phenotype of Tregs Within 4 weeks of T1DM diagnosis study the frequency and phenotype of insulin-specific autoreactive Tregs lymphocytes among CD4+ T lymphocytes in children with T1DM and compare these values with those of controls. These parameters will be analyzed by flow cytometry using immune cells from blood samples taken from the T1DM and control groups.
- Secondary Outcome Measures
Name Time Method HLA testing Within 4 weeks of T1DM diagnosis Description : the HLA of T1DM and controls will be analyzed by qPCR. This will make it possible to associate the results obtained during the analysis of the main criteria with the HLA of each individual.
Treg and Teffs transcriptome Within 4 weeks of T1DM diagnosis their transcriptome and TCR will be determined by single-cell transcriptomics analysis (scRNAseq).
Full TCR repertoire of Tregs and Teffs Within 4 weeks of T1DM diagnosis Following flow cytometry, the different repertoires will be compared between the DT1 and control groups.
Machine learning analysis Within 4 weeks of T1DM diagnosis Machine learning analysis of the data obtained (TCR, transcriptome, frequency and phenotype of insulin-specific Tregs and Teffs) to predict the relationship between TCR and functional properties of Tregs and Teffs in patients and controls
Isolate insulin-specific Tregs and Teffs cells Within 4 weeks of T1DM diagnosis Insulin-specific Tregs and Teffs cells will be isolated by flow cytometry
Trial Locations
- Locations (1)
Hôpital Necker Enfants Malades
🇫🇷Paris, France