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

Обзор

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

Подробное описание

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.

Вмешательства

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

Первичные конечные точки

• Frequency and phenotype of Tregs [Срок оценки: Within 4 weeks of T1DM diagnosis]

Вторичные конечные точки (5)

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

Критерии участия

Критерии включения

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.

Критерии исключения

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

Франция · 1 центр

• Hôpital Necker Enfants Malades — Paris

Публикации

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Идентификаторы

NCT: NCT06427421 · APHP230664 · 2024-A00696-41

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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