## Protocol Section
### Identification Module
**NCT ID:** NCT06427421

**Acronym:** CARegT1D

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

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

#### Organization Study ID Info
**ID:** APHP230664
#### Organization
**Class:** OTHER
**Full Name:** Assistance Publique - Hôpitaux de Paris
#### Secondary ID Infos
**Domain:** ID-RCB
**ID:** 2024-A00696-41
**Type:** OTHER
### Status Module
#### Completion Date
**Date:** 2026-08

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-23

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-16

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-08

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-23
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-16
**Study First Submit QC Date:** 2024-05-16
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Assistance Publique - Hôpitaux de Paris

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

### Description Module

**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.

### Conditions Module

**Conditions:**

- Type 1 Diabetes

**Keywords:**

- Type 1 Diabetes

- Regulatory T cells

- Pathophysiology of T1DM

### Design Module

#### Design Info

**Allocation:** NON_RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** BASIC_SCIENCE

#### Enrollment Info

**Count:** 80

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** children aged 6 to under 18 on the day of inclusion, with a recent diagnosis of type 1 diabetes

**Intervention Names:**

- Biological: Frequency of Treg and Teffs

- Biological: Phenotype of Treg and Teffs

- Biological: RNA seq analysis

- Biological: HLA typing

- Biological: beta-cell autoantibody dosage

**Label:** Newly diagnosed T1DM group

**Type:** OTHER

#### Arm Group 2

**Description:** children aged 6 to under 18 on the day of inclusion, with no history of type 1 diabetes

**Intervention Names:**

- Biological: Frequency of Treg and Teffs

- Biological: Phenotype of Treg and Teffs

- Biological: RNA seq analysis

- Biological: HLA typing

- Biological: beta-cell autoantibody dosage

- Biological: Glycated haemoglobin (HbA1C) dosage

- Biological: blood glucose dosage

- Biological: C-peptide dosage

**Label:** Control group

**Type:** OTHER

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Control group

- Newly diagnosed T1DM group

**Description:** additionnal blood sampling at inclusion

**Name:** Frequency of Treg and Teffs

**Type:** BIOLOGICAL

#### Intervention 2

**Arm Group Labels:**

- Control group

- Newly diagnosed T1DM group

**Description:** additionnal blood sampling at inclusion

**Name:** Phenotype of Treg and Teffs

**Type:** BIOLOGICAL

#### Intervention 3

**Arm Group Labels:**

- Control group

- Newly diagnosed T1DM group

**Description:** additionnal blood sampling at inclusion

**Name:** RNA seq analysis

**Type:** BIOLOGICAL

#### Intervention 4

**Arm Group Labels:**

- Control group

- Newly diagnosed T1DM group

**Description:** additionnal blood sampling at inclusion

**Name:** HLA typing

**Type:** BIOLOGICAL

#### Intervention 5

**Arm Group Labels:**

- Control group

- Newly diagnosed T1DM group

**Description:** additionnal blood sampling at inclusion

**Name:** beta-cell autoantibody dosage

**Type:** BIOLOGICAL

#### Intervention 6

**Arm Group Labels:**

- Control group

**Description:** additionnal blood sampling at inclusion

**Name:** Glycated haemoglobin (HbA1C) dosage

**Type:** BIOLOGICAL

#### Intervention 7

**Arm Group Labels:**

- Control group

**Description:** additionnal blood sampling at inclusion

**Name:** blood glucose dosage

**Type:** BIOLOGICAL

#### Intervention 8

**Arm Group Labels:**

- Control group

**Description:** additionnal blood sampling at inclusion

**Name:** C-peptide dosage

**Type:** BIOLOGICAL

### Outcomes Module

#### Primary Outcomes

**Description:** 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.

**Measure:** Frequency and phenotype of Tregs

**Time Frame:** Within 4 weeks of T1DM diagnosis

#### Secondary Outcomes

**Description:** 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.

**Measure:** HLA testing

**Time Frame:** Within 4 weeks of T1DM diagnosis

**Description:** Insulin-specific Tregs and Teffs cells will be isolated by flow cytometry

**Measure:** Isolate insulin-specific Tregs and Teffs cells

**Time Frame:** Within 4 weeks of T1DM diagnosis

**Description:** their transcriptome and TCR will be determined by single-cell transcriptomics analysis (scRNAseq).

**Measure:** Treg and Teffs transcriptome

**Time Frame:** Within 4 weeks of T1DM diagnosis

**Description:** Following flow cytometry, the different repertoires will be compared between the DT1 and control groups.

**Measure:** Full TCR repertoire of Tregs and Teffs

**Time Frame:** Within 4 weeks of T1DM diagnosis

**Description:** 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

**Measure:** Machine learning analysis

**Time Frame:** Within 4 weeks of T1DM diagnosis

### Eligibility Module

**Eligibility Criteria:** 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

**Maximum Age:** 18 Years

**Minimum Age:** 6 Years

**Sex:** ALL

**Standard Ages:**

- CHILD

- ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** jacques.beltrand@aphp.fr

**Name:** Jacques BELTRAND, MD, PhD

**Phone:** +33 1 40 61 53 20

**Role:** CONTACT

**Contact 2:**

**Email:** laure.choupeaux@aphp.fr

**Name:** Laure CHOUPEAUX, MSc

**Phone:** + 33 1 44 38 17 11

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Paris

**Contacts:**

***Contact 1:***

- **Email:** jacques.beltrand@aphp.fr

- **Name:** Jacques BELTRAND, MD, PhD

- **Phone:** +33 1 40 61 53 20

- **Role:** CONTACT

***Contact 2:***

- **Email:** laure.choupeaux@aphp.fr

- **Name:** Laure CHOUPEAUX, MSc

- **Phone:** + 33 1 44 38 17 11

- **Role:** CONTACT

***Contact 3:***

- **Name:** Jacques BELTRAND, MD, PhD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** France

**Facility:** Hôpital Necker Enfants Malades

**Zip:** 75015

#### Overall Officials

**Official 1:**

**Affiliation:** Institut National de la Santé Et de la Recherche Médicale, France

**Name:** Simon FILATREAU, PhD

**Role:** STUDY_DIRECTOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

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#### See Also Links

**Label:** Related Info

**URL:** https://diabetesatlas.org/data/

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000044882

- Term: Glucose Metabolism Disorders

- ID: D000008659

- Term: Metabolic Diseases

- ID: D000004700

- Term: Endocrine System Diseases

- ID: D000001327

- Term: Autoimmune Diseases

- ID: D000007154

- Term: Immune System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: BC19

- Name: Gland and Hormone Related Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC20

- Name: Immune System Diseases

### Condition Browse Module - Browse Leaves

- ID: M7115

- Name: Diabetes Mellitus

- Relevance: HIGH

- As Found: Diabetes

- ID: M7117

- Name: Diabetes Mellitus, Type 1

- Relevance: HIGH

- As Found: Type 1 Diabetes

- ID: M11639

- Name: Metabolic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M25403

- Name: Glucose Metabolism Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M4629

- Name: Autoimmune Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10200

- Name: Immune System Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000003920

- Term: Diabetes Mellitus

- ID: D000003922

- Term: Diabetes Mellitus, Type 1

### Intervention Browse Module - Ancestors

- ID: D000000894

- Term: Anti-Inflammatory Agents, Non-Steroidal

- ID: D000018712

- Term: Analgesics, Non-Narcotic

- ID: D000000700

- Term: Analgesics

- ID: D000018689

- Term: Sensory System Agents

- ID: D000018373

- Term: Peripheral Nervous System Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000000893

- Term: Anti-Inflammatory Agents

- ID: D000018501

- Term: Antirheumatic Agents

- ID: D000007155

- Term: Immunologic Factors

### Intervention Browse Module - Browse Branches

- Abbrev: Infl

- Name: Anti-Inflammatory Agents

- Abbrev: ARhu

- Name: Antirheumatic Agents

- Abbrev: Analg

- Name: Analgesics

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M207501

- Name: Chrysarobin

- Relevance: HIGH

- As Found: Palate

- ID: M4625

- Name: Autoantibodies

- Relevance: HIGH

- As Found: Loncastuximab Tesirine

- ID: M4217

- Name: Anti-Inflammatory Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4218

- Name: Anti-Inflammatory Agents, Non-Steroidal

- Relevance: LOW

- As Found: Unknown

- ID: M4032

- Name: Analgesics

- Relevance: LOW

- As Found: Unknown

- ID: M20786

- Name: Analgesics, Non-Narcotic

- Relevance: LOW

- As Found: Unknown

- ID: M20604

- Name: Antirheumatic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M10201

- Name: Immunologic Factors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000013883

- Term: Chrysarobin

- ID: D000001323

- Term: Autoantibodies

### Misc Info Module

- Version Holder: 2024-05-31
