The Role of Cytokines and Regulatory T Lymphocytes in Migraine Pathophysiology. (SIIM)

May 22, 2024 updated by: University Hospital, Clermont-Ferrand

Immune System, Inflammation, Migraine - The Role of Cytokines and Regulatory T Lymphocytes in Migraine Pathophysiology

Migraine is a frequent and debilitating neurologic disorder. It is more frequent in women, and more prevalent in patients with autoimmune and/or inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), Crohn's disease (CD), systemic lupus erythematosus (SLE) and endometriosis, whereas patients with long standing type 1 diabetes mellitus (T1DM) - an autoimmune but non inflammatory disease - seem to be less affected compared to the general population. Despite new migraine prevention treatments, a large number of patients remain unresponsive to currently available anti-migraine therapy and migraine pathophysiology remains unclear. Several peptides (calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase activating peptide-38 (PACAP-38), vasoactive intestinal polypeptide (VIP)) and hormones (estrogens, prolactin) and the immune system play an important role in migraine pathophysiology. Among T lymphocytes, regulatory T (Treg) cells suppress inflammation. Studies have evidenced higher levels of inflammatory molecules (cytokines) in migraine patients and have suggested decreased proportions of Treg cells in migraine, as well as in MS, RA, CD and SLE, whereas inflammation declines and Treg levels seem increased in long-standing T1DM. Inflammation, which participates in migraine pain, seems to be a common factor for migraine and these diseases. However, these studies display conflicting results and further investigation is required to better understand the mechanisms behind migraine.

In this study, the investigators will compare Treg levels, as well as identify Treg subpopulations and measure cytokine levels in migraine and migraine-free participants with and without an autoimmune/inflammatory disorder (MS, RA, CD, SLE, T1DM and endometriosis).

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Migraine is the 6th most frequent disease (14% of the population) and the second leading cause of disability worldwide. From puberty and onward, migraine is 2 to 3 times more frequent in women, which also suffer from more severe attacks. Migraine is also up to twice as prevalent in patients suffering from autoimmune or inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), Crohn disease (CD), systemic lupus erythematosus (SLE) and endometriosis, whereas patients with long standing type 1 diabetes mellitus (T1DM) - an autoimmune but non inflammatory disease - seem to be less affected compared to the general population.

Despite the identification of the role of peptides such as CGRP in migraine pathophysiology and the development of targetted anti-CGRP treatments, many patients remain unresponsive and the mechanisms behind migraine are still unclear.

The trigemino-vascular system is involved in the perception of migraine pain. Migraine occurs with trigemino-cervical neuron sensitization, leading to peptide secretion (such as CGRP, PACAP-38 and VIP), which induce neurogenic inflammation that is responsible for vasodilation, capillary leakage, oedema and further sensitization of the trigemino-vascular system, leading to amplified perception of migraine pain. CGRP, PACAP-38 and VIP infusions all induce migraine attacks in migraine patients, and only mild or no headache in healthy volunteers.

Sex hormones, prolactin and insulin are also involved in migraine pathophysiology, and the immune system, through cytokine production and immune cell dysregulations seems to also play a role in the pathogenesis of migraine. Both are closely related as sex hormone levels may have an influence on the levels of certain immune cell subtypes. Several pro-inflammatory cytokines (tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and interleukin (IL)-6) were shown to be elevated in migraine patients but also inflammatory diseases such as MS and endometriosis compared to controls and are associated with migraine pathophysiology. Inflammation seems to be a common factor for migraine and these diseases. However, these studies provide conflicting results and further investigation is needed to better understand the role of inflammation in migraine pathophysiology.

Among T lymphocytes, regulatory T (Treg) cells regulate inflammation by suppressing effector T cells through several suppressive mechanisms such as IL-10 secretion or the hydrolysis of pro-inflammatory and nociceptive adenosine triphosphate (ATP) into anti-inflammatory and anti-nociceptive adenosine by cluster of differentiation (CD) 39 and 73 enzymes on the Treg cell surface. Recent studies have suggested decreased Treg proportions in migraine patients, particularly CD 39 and CD 73-positive Treg cells, whereas Treg cells were shown to be increased in T1DM patients. This suggests the role of Treg cells in migraine, but further studies are needed.

In this study, the investigators aim to compare Treg levels, as well as identify Treg subpopulations and measure cytokine levels in migraine and migraine-free participants with and without an autoimmune/inflammatory disorder (MS, RA, CD, SLE, T1DM and endometriosis). This will provide better understanding of migraine pathophysiology and lead to the development of targeted and personalized treatment strategies, according to the immune pain profile and associated inflammatory diseases of migraine patients.

Study Type

Interventional

Enrollment (Estimated)

396

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • France
    • Aura
      • Clermont-Ferrand, Aura, France, 63000
        • CHU de Clermont-Ferrand - Service de Neurologie

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • female
  • 18 - 50 years of age
  • at least 50 kg

Exclusion Criteria:

  • menopause
  • type 2 diabetes
  • pregnancy (or delivery < 3 months)
  • breast feeding
  • hysterectomy or adnexectomy
  • characterized immune deficiency
  • active cancer (or remission < 1 year)
  • bone marrow or solid organ transplant
  • hormone therapy (other than birth control)
  • migraine attack within 12 hours before or after blood test
  • person under guardianship

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Migraine - no autoimmune/inflammatory disease
Migraine - no autoimmune/inflammatory disease group
Biological: Blood test
1 blood test of maximum 40 millilitres per patient
Experimental: No migraine - no autoimmune/inflammatory disease
No migraine - no autoimmune/inflammatory disease group
Biological: Blood test
1 blood test of maximum 40 millilitres per patient
Experimental: No migraine - autoimmune/inflammatory disease (MS, RA, CD, SLE, T1DM, endometriosis)
No migraine - autoimmune/inflammatory disease (MS, RA, CD, SLE, T1DM, endometriosis) group
Biological: Blood test
1 blood test of maximum 40 millilitres per patient
Experimental: Migraine - autoimmune/inflammatory disease (MS, RA, CD, SLE, T1DM, endometriosis)
Migraine - autoimmune/inflammatory disease (MS, RA, CD, SLE, T1DM, endometriosis) group
Biological: Blood test
1 blood test of maximum 40 millilitres per patient

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Treg cell levels in cell/microliter (cell/µL)
Time Frame: Once, at inclusion
To measure Treg cell levels in migraine and migraine-free participants, with and without autoimmune/inflammatory diseases (MS, RA, CD, SLE, endometriosis, T1DM) using flow cytometry
Once, at inclusion
Treg cell levels in percentage (%) of white blood cells
Time Frame: Once, at inclusion
To measure Treg cell levels in migraine and migraine-free participants, with and without autoimmune/inflammatory diseases (MS, RA, CD, SLE, endometriosis, T1DM) using flow cytometry
Once, at inclusion
Age in years
Time Frame: Once, at inclusion
Age at inclusion
Once, at inclusion
Weight in kilograms (kg)
Time Frame: Once, at inclusion
Weight on scales during inclusion visit
Once, at inclusion
Score on the Hospital Anxiety and Depression Scale
Time Frame: Once, at inclusion
Score to be answered at inclusion to determine anxiety and depression levels : ranges from 0 to 21 for each (anxiety and depression). A score of 11 and above ascertains anxiety or depression. Licence n° 2403391 with Mapi Research Trust.
Once, at inclusion
Score on the Headache Impact Test
Time Frame: Once, at inclusion
Score to be answered at inclusion to determine the impact of headache on patients' daily life, ranging from 36 to 78. The higher the score, the higher the impact of headache on daily life. Licence to be signed shortly with QualityMetrics
Once, at inclusion
Migraine diagnostic criteria from the International Classification of Headache Disorders 3rd edition (ICHD-3)
Time Frame: Once, at inclusion
To be completed at inclusion to confirm migraine diagnosis. No licence needed
Once, at inclusion
Number of headache days per month in days/month
Time Frame: Once, at inclusion
Number of days with a headache to determine whether migraine is episodic or chronic (average during last 3 months)
Once, at inclusion
White blood cell count in giga/liter (G/L)
Time Frame: Once, at inclusion
To measure the absolute white blood cell count to determine the percentage of Treg cells
Once, at inclusion
Sex (female, male)
Time Frame: Once, at inclusion
For sex repartition
Once, at inclusion
Date of last menstrual period as a date in the form: day/month/year
Time Frame: Once, at inclusion
Date of last menstrual period start day to measure the impact of the menstrual cycle on Treg levels
Once, at inclusion
Human chorionic gonadotropin subunit beta level in milli-international units per milliliter (mIU/mL)
Time Frame: Once, at inclusion
To insure exclusion of pregnant women
Once, at inclusion
Height in meters (m)
Time Frame: Once, at inclusion
Measured at inclusion
Once, at inclusion
Body mass index (BMI) in kilogram per square meter (kg/m2)
Time Frame: Once, at inclusion
Weight in kilograms and height in meters will be combined to determine the body mass index in kilogram per square meter
Once, at inclusion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cytokine levels in picogram per milliliter (pg/mL)
Time Frame: Once, at inclusion
To measure cytokine levels (interleukin 1b, interleukin 2, interleukin 6, interleukin 10, interleukin 12, interleukin 17, interleukin 18, interleukin 21, interleukin 23, interleukin 35, tumor necrosis factor a, interferon g and transforming growth factor b) using a LUMINEX method
Once, at inclusion
Progesterone in nanogram per milliliter (ng/mL)
Time Frame: Once, at inclusion
To determine correlation with Treg cell levels
Once, at inclusion
Estrogen in picogram per milliliter (pg/mL)
Time Frame: Once, at inclusion
To determine correlation with Treg cell levels
Once, at inclusion
Follicle stimulating hormone (FSH) in milli-international units per milliliter (mIU/mL)
Time Frame: Once, at inclusion
To determine the correlation between the menstrual cycle period and Treg cell levels
Once, at inclusion
Luteinizing hormone in international units per liter (IU/L)
Time Frame: Once, at inclusion
To determine the correlation between the menstrual cycle period and Treg cell levels
Once, at inclusion
Levels of C-reactive protein (CRP) in milligram per liter (mg/L)
Time Frame: Once, at inclusion
To measure the general level of inflammation
Once, at inclusion
Fasting blood glucose concentration in gram per liter (g/L)
Time Frame: Once, at inclusion
To determine the correlation between sugar levels and Treg cell levels
Once, at inclusion
Insulin levels in milligram per deciliter (mg/dL)
Time Frame: Once, at inclusion
To determine the correlation between insulin levels and Treg cell levels
Once, at inclusion
Prolactin levels in nanogram per milliliter (ng/mL)
Time Frame: Once, at inclusion
To determine the correlation between the presence of migraine and prolactin levels
Once, at inclusion
Calcitonin gene-related peptide (CGRP) in picogram per milliliter (pg/mL)
Time Frame: Once, at inclusion
To study association between CGRP levels and migraine
Once, at inclusion
Vasoactive intestinal polypeptide (VIP) in picogram per milliliter (pg/mL)
Time Frame: Once, at inclusion
To study association between VIP levels and migraine
Once, at inclusion
Pituitary adenylate cyclase-activating polypeptide (PACAP) levels in nanogram per milliliter (ng/mL)
Time Frame: Once, at inclusion
To study association between PACAP levels and migraine
Once, at inclusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Clermont-Ferrand

Investigators

  • Principal Investigator: Xavier MOISSET, University Hospital, Clermont-Ferrand

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 15, 2024

Primary Completion (Estimated)

April 30, 2027

Study Completion (Estimated)

April 30, 2027

Study Registration Dates

First Submitted

April 30, 2024

First Submitted That Met QC Criteria

May 22, 2024

First Posted (Actual)

May 23, 2024

Study Record Updates

Last Update Posted (Actual)

May 23, 2024

Last Update Submitted That Met QC Criteria

May 22, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RBHP 2023 STUCHFIELD
  • 2023-A01503-42 (Other Identifier: ANSM)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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