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In Vitro Effect Study of Interleukin-2 Muteins on Regulatory T Cells of Patients With Different Autoimmune, Allo-immune or Inflammatory Diseases (MuTreg)

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ClinicalTrials.gov Identifier: NCT05544448
Recruitment Status : Not yet recruiting
First Posted : September 16, 2022
Last Update Posted : September 16, 2022
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

Interleukin 2 (IL-2) is a critical cytokine for the survival and function of regulatory T cells (LTreg). This cytokine has a dual role in the immune system. IL-2 stimulates immune responses by acting on the intermediate affinity IL-2R receptor, IL-2Rβγ, expressed by conventional T cells (LTconv) during activation, but also contributes to the inhibition of immune responses via LTreg that express the high affinity receptor IL-2Rαβγ.

This difference in IL-2 receptor affinity for IL-2 has led to the development of low-dose IL-2 therapy to stimulate LTreg and improve control of excessive inflammation in autoimmune (AID), inflammatory or alloimmune diseases Low-dose IL-2 therapy is being studied in several of these diseases such as systemic lupus erythematosus, type 1 diabetes, alopecia, HCV (hepatitis C virus)-induced vasculitis, atopic dermatitis and chronic allo-transplantation-related graft-versus-host disease (GVHD).

Some of these studies have shown an increase in LTreg numbers and an improvement in certain clinical signs.

To improve LTreg targeting in autoimmune diseases, inflammatory diseases or GVHD, mutated IL-2s (muteins) have been developed with selective LTreg agonist properties.

These IL-2 muteins are linked to an Fc fragment to increase their half-life. Two IL-2 variants (IL-2Vs)-Fc preferentially stimulate STAT5 phosphorylation in LTregs compared to conventional FoxP3- (LTconv) CD4+ or CD8+ T cells


Condition or disease Intervention/treatment Phase
Autoimmune Diseases Inflammatory Disease Acquired Bone Marrow Aplasia Systemic Lupus Erythematosus Multiple Sclerosis Gvhd Rheumatoid Arthritis Autoimmune Thyroiditis Vitiligo Alopecia Atopic Dermatitis Other: Blood sample taken at a single time point Not Applicable

Detailed Description:

Hypothesis:

In order to confirm that this differential effect of IL-2 muteins, already established in non-diseased controls, is also observed in patients with autoimmune diseases, inflammatory diseases or GVHD, a pilot in vitro study should be conducted on a small number of patient's blood samples (5 or 10 depending on the pathology).

Objective :

Conduct a multicentre pilot study to confirm the hypothesis that IL-2 muteins preferentially activate the STAT5 pathway in LTreg compared to LTconv in patients with GVHD, acquired bone marrow aplasia, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, autoimmune thyroiditis, vitiligo, alopecia or atopic dermatitis

Method:

At the inclusion, patients will have a blood sample collected for in vitro research purposes. Their clinical data will also be collected.

Conclusion This trial should provide in vitro proof-of-principle of the efficacy of IL-2 muteins on LTreg and could eventually lead to a therapeutic trial

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This study is a multicenter, open-label, non-controlled, non-randomized in vitro study.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: n Vitro Effect Study of Interleukin-2 Muteins on Regulatory T Cells of Patients With Different Autoimmune, Allo-immune or Inflammatory Diseases
Estimated Study Start Date : October 15, 2022
Estimated Primary Completion Date : April 15, 2023
Estimated Study Completion Date : April 15, 2023



Intervention Details:
  • Other: Blood sample taken at a single time point
    At inclusion, a blood sample will be taken for research purpose


Primary Outcome Measures :
  1. the percentage of phosphorylated STAT5 in LTresg compared to LTconv after incubation with IL-2 muteins [ Time Frame: At inclusion ]
    The measurement method is based on the quantification of the phosphorylated STAT5 molecule in LTconv and LTreg by flow cytometry after incubating the cells with IL-2 or IL-2 muteins



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Inclusion criteria common to all patients in different departments:
  • Age18 years
  • Affiliated to social security or entitled to
  • Patient who has been informed of the study and has signed a free and informed consent

Inclusion criteria specific by department:

Inclusion criteria for Clinical Hematology Department:

  • Patient with GVHD following allogeneic hematopoietic stem cell transplantation (HSC)
  • Or with acquired bone marrow suppression
  • Lymphocytosis > 0.5 G/L

Inclusion criteria for Nephrology and Transplantation department:

- Patient with systemic lupus erythematosus (ACR classification criteria)

Inclusion criteria for Neurology department:

- Patient with multiple sclerosis (criteria of Mc Donald 2017)

Inclusion criteria for Rheumatology Department:

- Patient with rheumatoid arthritis (ACR classification criteria)

Inclusion criteria for Internal Medicine-Endocrinology Department:

- Patient with Basedow disease, Hashimoto's thyroiditis

Inclusion criteria for Dermatology Department:

- Patient with vitiligo or alopecia areata or atopic dermatitis

Exclusion Criteria:

Non-inclusion criteria common to all patients:

  • Patient under guardianship, curatorship or judicial protection
  • Pregnant, parturient or breastfeeding woman
  • Patient deprived of liberty
  • Patient hospitalized without consent
  • Patient admitted to a health or social institution for purposes other than research
  • Minor patient
  • Adult patient unable to express consent
  • Refusal to participate
  • Patient on AME

Non-inclusion criteria specific by department:

Non-inclusion criteria for Clinical Hematology Department:

  • Ongoing treatment with high doses (>1 mg/kg/d) of systemic corticosteroid therapy
  • Ongoing treatment with JAK inhibitors

Non-inclusion criteria for Nephrology and Transplantation Department:

  • Ongoing treatment with doses >10 mg/d Prednisone
  • Ongoing treatment with Cellcept, Endoxan, Imurel, Belimumab, Anti-CD20, Methotrexate
  • Ongoing treatment with JAK inhibitors

Non-inclusion criteria for Neurology Department:

  • Treatment with systemic corticosteroid therapy, Fingolimod or Teriflunomide
  • Ongoing treatment with JAK inhibitors
  • Lymphocytosis < 0.5 G/L

Non-inclusion criteria for Rheumatology Department:

  • Ongoing treatment with doses >15 mg/d Prednisone
  • Treatment with Rituximab or Tocilizumab
  • Ongoing treatment with JAK inhibitors
  • Lymphocytosis < 0.5 G/L

Non-inclusion criteria for Internal Medicine - Endocrinology Department:

  • Ongoing immunosuppressive therapy
  • Ongoing treatment with JAK inhibitors

Non-inclusion criteria for Dermatology Department:

  • Ongoing treatment with Methotrexate
  • Ongoing treatment with JAK inhibitors
  • Ongoing treatment with doses >10 mg/d prednisone

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05544448


Contacts
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Contact: Philippe REMY, MD 01 49 81 24 59 ext 33 Philippe.remy@aphp.fr
Contact: José Cohen, PHD 01 49 81 44 75 ext 33 jose.cohen@inserm.fr

Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT05544448    
Other Study ID Numbers: APHP 220507
First Posted: September 16, 2022    Key Record Dates
Last Update Posted: September 16, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Autoimmune Diseases
Inflammation
Graft vs Host Disease
T-lymphocytes, Regulatory
Interleukin-2
Additional relevant MeSH terms:
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Multiple Sclerosis
Anemia, Aplastic
Dermatitis
Lupus Erythematosus, Systemic
Alopecia
Vitiligo
Thyroiditis
Thyroiditis, Autoimmune
Hashimoto Disease
Autoimmune Diseases
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Immune System Diseases
Connective Tissue Diseases
Skin Diseases
Hypotrichosis
Hair Diseases
Pathological Conditions, Anatomical
Hypopigmentation
Pigmentation Disorders
Thyroid Diseases
Endocrine System Diseases
Anemia
Hematologic Diseases
Bone Marrow Failure Disorders
Bone Marrow Diseases