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

Pain Clinical Trial

— SIIM  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06426316
• Other study ID #: RBHP 2023 STUCHFIELD
• Secondary ID: 2023-A01503-42
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 15, 2024
• Est. completion date: April 30, 2027

Study information

• Verified date: May 2024
• Source: University Hospital, Clermont-Ferrand
• Contact: Lise LACLAUTRE
• Phone: 334.73.754.963
• Email: promo_interne_drci[@]chu-clermontferrand.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 396
• Est. completion date: April 30, 2027
• Est. primary completion date: April 30, 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Autoimmune Diseases
• Crohn Disease
• Endometriosis
• Lupus Erythematosus
• Migraine Disorders
• Multiple Sclerosis
• Pain
• Rheumatoid Arthritis

Intervention

Biological:
• Blood test
1 blood test of maximum 40 millilitres per patient

Locations

Country	Name	City	State
France	CHU de Clermont-Ferrand - Service de Neurologie	Clermont-Ferrand	Aura

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Clermont-Ferrand

Country where clinical trial is conducted

France, 

References & Publications (21)

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Al-Karagholi MA, Kalatharan V, Ghanizada H, Gram C, Dussor G, Ashina M. Prolactin in headache and migraine: A systematic review of clinical studies. Cephalalgia. 2023 Feb;43(2):3331024221136286. doi: 10.1177/03331024221136286. — View Citation

Arumugam M, Parthasarathy V. Reduction of CD4(+)CD25(+) regulatory T-cells in migraine: Is migraine an autoimmune disorder? J Neuroimmunol. 2016 Jan 15;290:54-9. doi: 10.1016/j.jneuroim.2015.11.015. Epub 2015 Nov 28. — View Citation

Ashina M. Migraine. N Engl J Med. 2020 Nov 5;383(19):1866-1876. doi: 10.1056/NEJMra1915327. No abstract available. — View Citation

Bhoi SK, Kalita J, Misra UK. Metabolic syndrome and insulin resistance in migraine. J Headache Pain. 2012 Jun;13(4):321-6. doi: 10.1007/s10194-012-0416-y. Epub 2012 Jan 26. — View Citation

Faraji F, Shojapour M, Farahani I, Ganji A, Mosayebi G. Reduced regulatory T lymphocytes in migraine patients. Neurol Res. 2021 Aug;43(8):677-682. doi: 10.1080/01616412.2021.1915077. Epub 2021 Apr 14. — View Citation

Gobel K, Ruck T, Meuth SG. Cytokine signaling in multiple sclerosis: Lost in translation. Mult Scler. 2018 Apr;24(4):432-439. doi: 10.1177/1352458518763094. Epub 2018 Mar 7. — View Citation

Hagen K, Asvold BO, Midthjell K, Stovner LJ, Zwart JA, Linde M. Inverse relationship between type 1 diabetes mellitus and migraine. Data from the Nord-Trondelag Health Surveys 1995-1997 and 2006-2008. Cephalalgia. 2018 Mar;38(3):417-426. doi: 10.1177/0333102417690488. Epub 2017 Jan 23. — View Citation

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Moisset X, Bommelaer G, Boube M, Ouchchane L, Goutte M, Dapoigny M, Dallel R, Guttmann A, Clavelou P, Buisson A. Migraine prevalence in inflammatory bowel disease patients: A tertiary-care centre cross-sectional study. Eur J Pain. 2017 Oct;21(9):1550-1560. doi: 10.1002/ejp.1056. Epub 2017 May 16. — View Citation

Moisset X, Giraud P, Dallel R. Migraine in multiple sclerosis and other chronic inflammatory diseases. Rev Neurol (Paris). 2021 Sep;177(7):816-820. doi: 10.1016/j.neurol.2021.07.005. Epub 2021 Jul 27. — View Citation

Okimura H, Tanaka Y, Fujii M, Shimura K, Maeda E, Ito F, Khan KN, Nakamura Y, Mori T, Kitawaki J. Changes in the proportion of regulatory T cell subpopulations during menstrual cycle and early pregnancy. Am J Reprod Immunol. 2022 Dec;88(6):e13636. doi: 10.1111/aji.13636. Epub 2022 Oct 21. — View Citation

Pellesi L, Al-Karagholi MA, De Icco R, Coskun H, Elbahi FA, Lopez-Lopez C, Snellman J, Hannibal J, Amin FM, Ashina M. Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches: A Randomized Clinical Trial. JAMA Netw Open. 2021 Aug 2;4(8):e2118543. doi: 10.1001/jamanetworkopen.2021.18543. — View Citation

Perini F, D'Andrea G, Galloni E, Pignatelli F, Billo G, Alba S, Bussone G, Toso V. Plasma cytokine levels in migraineurs and controls. Headache. 2005 Jul-Aug;45(7):926-31. doi: 10.1111/j.1526-4610.2005.05135.x. — View Citation

Schetters STT, Gomez-Nicola D, Garcia-Vallejo JJ, Van Kooyk Y. Neuroinflammation: Microglia and T Cells Get Ready to Tango. Front Immunol. 2018 Jan 25;8:1905. doi: 10.3389/fimmu.2017.01905. eCollection 2017. — View Citation

Shi JL, Zheng ZM, Chen M, Shen HH, Li MQ, Shao J. IL-17: an important pathogenic factor in endometriosis. Int J Med Sci. 2022 Apr 11;19(4):769-778. doi: 10.7150/ijms.71972. eCollection 2022. — View Citation

Stovner LJ, Hagen K, Linde M, Steiner TJ. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain. 2022 Apr 12;23(1):34. doi: 10.1186/s10194-022-01402-2. — View Citation

Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008 Jul;8(7):523-32. doi: 10.1038/nri2343. — View Citation

Viisanen T, Gazali AM, Ihantola EL, Ekman I, Nanto-Salonen K, Veijola R, Toppari J, Knip M, Ilonen J, Kinnunen T. FOXP3+ Regulatory T Cell Compartment Is Altered in Children With Newly Diagnosed Type 1 Diabetes but Not in Autoantibody-Positive at-Risk Children. Front Immunol. 2019 Jan 22;10:19. doi: 10.3389/fimmu.2019.00019. eCollection 2019. — View Citation

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Yang MH, Wang PH, Wang SJ, Sun WZ, Oyang YJ, Fuh JL. Women with endometriosis are more likely to suffer from migraines: a population-based study. PLoS One. 2012;7(3):e33941. doi: 10.1371/journal.pone.0033941. Epub 2012 Mar 19. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treg cell levels in cell/microliter (cell/µL)	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
Primary	Treg cell levels in percentage (%) of white blood cells	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
Primary	Age in years	Age at inclusion	Once, at inclusion
Primary	Weight in kilograms (kg)	Weight on scales during inclusion visit	Once, at inclusion
Primary	Score on the Hospital Anxiety and Depression Scale	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
Primary	Score on the Headache Impact Test	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
Primary	Migraine diagnostic criteria from the International Classification of Headache Disorders 3rd edition (ICHD-3)	To be completed at inclusion to confirm migraine diagnosis. No licence needed	Once, at inclusion
Primary	Number of headache days per month in days/month	Number of days with a headache to determine whether migraine is episodic or chronic (average during last 3 months)	Once, at inclusion
Primary	White blood cell count in giga/liter (G/L)	To measure the absolute white blood cell count to determine the percentage of Treg cells	Once, at inclusion
Primary	Sex (female, male)	For sex repartition	Once, at inclusion
Primary	Date of last menstrual period as a date in the form: day/month/year	Date of last menstrual period start day to measure the impact of the menstrual cycle on Treg levels	Once, at inclusion
Primary	Human chorionic gonadotropin subunit beta level in milli-international units per milliliter (mIU/mL)	To insure exclusion of pregnant women	Once, at inclusion
Primary	Height in meters (m)	Measured at inclusion	Once, at inclusion
Primary	Body mass index (BMI) in kilogram per square meter (kg/m2)	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	Cytokine levels in picogram per milliliter (pg/mL)	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
Secondary	Progesterone in nanogram per milliliter (ng/mL)	To determine correlation with Treg cell levels	Once, at inclusion
Secondary	Estrogen in picogram per milliliter (pg/mL)	To determine correlation with Treg cell levels	Once, at inclusion
Secondary	Follicle stimulating hormone (FSH) in milli-international units per milliliter (mIU/mL)	To determine the correlation between the menstrual cycle period and Treg cell levels	Once, at inclusion
Secondary	Luteinizing hormone in international units per liter (IU/L)	To determine the correlation between the menstrual cycle period and Treg cell levels	Once, at inclusion
Secondary	Levels of C-reactive protein (CRP) in milligram per liter (mg/L)	To measure the general level of inflammation	Once, at inclusion
Secondary	Fasting blood glucose concentration in gram per liter (g/L)	To determine the correlation between sugar levels and Treg cell levels	Once, at inclusion
Secondary	Insulin levels in milligram per deciliter (mg/dL)	To determine the correlation between insulin levels and Treg cell levels	Once, at inclusion
Secondary	Prolactin levels in nanogram per milliliter (ng/mL)	To determine the correlation between the presence of migraine and prolactin levels	Once, at inclusion
Secondary	Calcitonin gene-related peptide (CGRP) in picogram per milliliter (pg/mL)	To study association between CGRP levels and migraine	Once, at inclusion
Secondary	Vasoactive intestinal polypeptide (VIP) in picogram per milliliter (pg/mL)	To study association between VIP levels and migraine	Once, at inclusion
Secondary	Pituitary adenylate cyclase-activating polypeptide (PACAP) levels in nanogram per milliliter (ng/mL)	To study association between PACAP levels and migraine	Once, at inclusion