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

Overview

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.

Interventions

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

Primary outcome measures

• Frequency and phenotype of Tregs [Time frame: Within 4 weeks of T1DM diagnosis]

Secondary outcome measures (5)

• HLA testing [Time frame: Within 4 weeks of T1DM diagnosis]
• Isolate insulin-specific Tregs and Teffs cells [Time frame: Within 4 weeks of T1DM diagnosis]
• Treg and Teffs transcriptome [Time frame: Within 4 weeks of T1DM diagnosis]
• Full TCR repertoire of Tregs and Teffs [Time frame: Within 4 weeks of T1DM diagnosis]
• Machine learning analysis [Time frame: Within 4 weeks of T1DM diagnosis]

Eligibility criteria

Inclusion criteria

Newly diagnosed T1DM group:

• Age ≥ 2 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 ≥ 2 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 oral or intravenous corticosteriods 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 oral or intravenous corticosteriods in the month prior to blood sampling
• Contraindication to the use of anaesthetic cream for blood sampling

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

France · 1 center

• Hôpital Necker Enfants Malades — Paris

Publications

• 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 chil PMID 30483858
• Mobasseri M, Shirmohammadi M, Amiri T, Vahed N, Hosseini Fard H, Ghojazadeh M. Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis. Health Promot Perspect. 2020 Mar 30;10(2):98-115. doi: 10.34172/hpp.2020.18. eCollection 2020. PMID 32296622
• 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. PMID 30657336
• Miller KM, Foster NC, Beck RW, Bergenstal RM, DuBose SN, DiMeglio LA, Maahs DM, Tamborlane WV; T1D Exchange Clinic Network. Current state of type 1 diabetes treatment in the U.S.: updated data from the T1D Exchange clinic registry. Diabetes Care. 2015 Jun;38(6):971-8. doi: 10.2337/dc15-0078. PMID 25998289
• Bougneres PF, Carel JC, Castano L, Boitard C, Gardin JP, Landais P, Hors J, Mihatsch MJ, Paillard M, Chaussain JL, et al. Factors associated with early remission of type I diabetes in children treated with cyclosporine. N Engl J Med. 1988 Mar 17;318(11):663-70. doi: 10.1056/NEJM198803173181103. PMID 3125434
• Parving HH, Tarnow L, Nielsen FS, Rossing P, Mandrup-Poulsen T, Osterby R, Nerup J. Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study. Diabetes Care. 1999 Mar;22(3):478-83. doi: 10.2337/diacare.22.3.478. PMID 10097932
• Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, Gitelman SE, Gottlieb PA, Krischer JP, Linsley PS, Marks JB, Moore W, Moran A, Rodriguez H, Russell WE, Schatz D, Skyler JS, Tsalikian E, Wherrett DK, Ziegler AG, Greenbaum CJ; Type 1 Diabetes TrialNet Study Group. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019 Aug 15;381(7):603-613. PMID 31180194
• Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005 Jun 23;352(25):2598-608. d PMID 15972866

Identifiers

NCT: NCT06427421 · APHP230664 · 2024-A00696-41

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗