Characterization of Autoreactive Regulatory and Conventional CD4 T Cells in Recent Onset Type 1 Diabetes and Control Individuals

Type 1 Diabetes Clinical Trial

— CARegT1D  

Official title:

Characterization of Autoreactive Regulatory and Conventional CD4 T Cells in Recent Onset Type 1 Diabetes and Control Individuals

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06427421
• Other study ID #: APHP230664
• Secondary ID: 2024-A00696-41
• Status: Not yet recruiting
• Phase: N/A
• Start date: June 2024
• Est. completion date: August 2026

Study information

• Verified date: May 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Jacques BELTRAND, MD, PhD
• Phone: +33 1 40 61 53 20
• Email: jacques.beltrand[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Not yet recruiting
• Enrollment: 80
• Est. completion date: August 2026
• Est. primary completion date: August 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 18 Years

Eligibility

Inclusion Criteria:

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. Exclusion Criteria:

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes

Intervention

Biological:
• Frequency of Treg and Teffs
additionnal blood sampling at inclusion
• Phenotype of Treg and Teffs
additionnal blood sampling at inclusion
• RNA seq analysis
additionnal blood sampling at inclusion
• HLA typing
additionnal blood sampling at inclusion
• beta-cell autoantibody dosage
additionnal blood sampling at inclusion
• Glycated haemoglobin (HbA1C) dosage
additionnal blood sampling at inclusion
• blood glucose dosage
additionnal blood sampling at inclusion
• C-peptide dosage
additionnal blood sampling at inclusion

Locations

Country	Name	City	State
France	Hôpital Necker Enfants Malades	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (18)

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Foster NC, Beck RW, Miller KM, Clements MA, Rickels MR, DiMeglio LA, Maahs DM, Tamborlane WV, Bergenstal R, Smith E, Olson BA, Garg SK. State of Type 1 Diabetes Management and Outcomes from the T1D Exchange in 2016-2018. Diabetes Technol Ther. 2019 Feb;21(2):66-72. doi: 10.1089/dia.2018.0384. Epub 2019 Jan 18. Erratum In: Diabetes Technol Ther. 2019 Apr;21(4):230. — View Citation

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Patterson CC, Harjutsalo V, Rosenbauer J, Neu A, Cinek O, Skrivarhaug T, Rami-Merhar B, Soltesz G, Svensson J, Parslow RC, Castell C, Schoenle EJ, Bingley PJ, Dahlquist G, Jarosz-Chobot PK, Marciulionyte D, Roche EF, Rothe U, Bratina N, Ionescu-Tirgoviste C, Weets I, Kocova M, Cherubini V, Rojnic Putarek N, deBeaufort CE, Samardzic M, Green A. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study. Diabetologia. 2019 Mar;62(3):408-417. doi: 10.1007/s00125-018-4763-3. Epub 2018 Nov 28. — View Citation

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* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequency and phenotype of Tregs	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.	Within 4 weeks of T1DM diagnosis
Secondary	HLA testing	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.	Within 4 weeks of T1DM diagnosis
Secondary	Isolate insulin-specific Tregs and Teffs cells	Insulin-specific Tregs and Teffs cells will be isolated by flow cytometry	Within 4 weeks of T1DM diagnosis
Secondary	Treg and Teffs transcriptome	their transcriptome and TCR will be determined by single-cell transcriptomics analysis (scRNAseq).	Within 4 weeks of T1DM diagnosis
Secondary	Full TCR repertoire of Tregs and Teffs	Following flow cytometry, the different repertoires will be compared between the DT1 and control groups.	Within 4 weeks of T1DM diagnosis
Secondary	Machine learning analysis	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	Within 4 weeks of T1DM diagnosis

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