BACKGROUND: The QuantiFERON®-Monitor (QFM) is an assay that measures interferon-γ production and was developed to provide an objective marker of complex immune response. In this study, we evaluated the use of the QFM test in patients with two forms of multiple sclerosis (MS), relapsing-remitting form treated with fingolimod (fMS) and secondarily progressive form not treated pharmacologically (pMS), and in healthy controls (HC). We hypothesized that IFN-γ levels would be lower in those subjects who are relatively more immunosuppressed and higher in those with normal or activated immune function. METHODS: This single-center observational study was conducted from November 2020 to October 2021 and compared results in three groups of patients: 86 healthy controls, 96 patients with pMS, and 78 fMS. Combination of lyophilized stimulants was added to 1 ml heparinized whole blood within 8 hr of collection. Plasmatic IFN-γ was measured using the ELISA kit for the QFM and data were obtained in IU/ml. RESULTS: The results showed that controls had nearly 2-fold higher levels of IFN-γ (QFM score) in median (q25, q75) 228.00 (112.20, 358.67) than the MS patient groups: pMS 144.80 (31.23, 302.00); fMS 130.50 (39.95, 217.07) which is statistically significant difference P-value: HC vs. pMS = 0.0071; HC vs. fMS = 0.0468. This result was also confirmed by a validation analysis to exclude impact of variable factors, such as disease duration and Expanded Disability Status Scale scores. CONCLUSIONS: Results showed that controls had higher levels of IFN-γ production than the MS patient groups and suggest that MS patients included in this study have a lower ability of immune system activation than HC. Results confirm that fingolimod is able to suppress production of IFN-γ. The fact that the QFM score of MS patients is significantly lower than that of HC may indicate a dysfunctional state of the immune system in baseline conditions.

Department of Clinical Immunology and Allergology University Hospital Hradec Králové Hradec Králové Czech Republic

Department of Neurology Faculty of Medicine and University Hospital Hradec Králové Charles University Prague Hradec Králové Czech Republic

Department of Neurology Faculty of Medicine and University Hospital Plzen Charles University Prague Plzeň Czech Republic

Department of Neurology University Hospital and Masaryk University Brno Czech Republic

See more in PubMed

Yamasaki R., Kira J.-I. Multiple sclerosis. In: Sango K., Yamauchi J., Ogata T., Susuki K., editors. Myelin . Vol. 1190. Springer; 2019. pp. 217–247. DOI

Yadav S. K., Mindur J. E., Ito K., Dhib-Jalbut S. Advances in the immunopathogenesis of multiple sclerosis. Current Opinion in Neurology . 2015;28(3):206–219. doi: 10.1097/WCO.0000000000000205. PubMed DOI

Macaron G., Ontaneda D. Diagnosis and management of progressive multiple sclerosis. Biomedicines . 2019;7(3) doi: 10.3390/biomedicines7030056.56 PubMed DOI PMC

Hemmer B., Kerschensteiner M., Korn T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. The Lancet Neurology . 2015;14(4):406–419. doi: 10.1016/S1474-4422(14)70305-9. PubMed DOI

Navikas V., Link H. Review: cytokines and the pathogenesis of multiple sclerosis. Journal of Neuroscience Research . 1996;45(4):322–333. doi: 10.1002/(SICI)1097-4547(19960815)45:4<322::AID-JNR1>3.0.CO;2-B. PubMed DOI

Gardiner B. J., Lee S. J., Cristiano Y., et al. Evaluation of Quantiferon®-Monitor as a biomarker of immunosuppression and predictor of infection in lung transplant recipients. Transplant Infectious Disease . 2021;23(3) doi: 10.1111/tid.13550.e13550 PubMed DOI

Feng J.-Y., Ho L.-I., Chuang F.-Y., et al. Depression and recovery of IL-17A secretion in mitogen responses in patients with active tuberculosis—a prospective observational study. Journal of The Formosan Medical Association . 2021;120(4):1080–1089. doi: 10.1016/j.jfma.2020.09.012. PubMed DOI

Sood S., Cundall D., Yu L., et al. A novel biomarker of immune function and initial experience in a transplant population. Transplantation . 2014;97(8):e50–e51. doi: 10.1097/TP.0000000000000078. PubMed DOI

Douglas A. P., Yu L., Sundararajan V., et al. The QuantiFERON Monitor® assay is predictive of infection post allogeneic hematopoietic cell transplantation. Transplant Infectious Disease . 2020;22(3) doi: 10.1111/tid.13260.e13260 PubMed DOI

Margeta I., Mareković I., Pešut A., et al. Evaluation of cell-mediated immune response by QuantiFERON Monitor assay in kidney transplant recipients presenting with infective complications. Medicine . 2020;99(27) doi: 10.1097/MD.0000000000021010.e21010 PubMed DOI PMC

Yong M. K., Cameron P. U., Spelman T., et al. Quantifying adaptive and innate immune responses in HIV-infected participants using a novel high throughput assay. PLOS ONE . 2016;11(12) doi: 10.1371/journal.pone.0166549.e0166549 PubMed DOI PMC

Mangioni D., Oggioni M., Chatenoud L., et al. Prognostic value of mid-region proadrenomedullin and in vitro interferon gamma production for in-hospital mortality in patients with COVID-19 pneumonia and respiratory failure: an observational prospective study. Viruses . 2022;14(8) doi: 10.3390/v14081683.1683 PubMed DOI PMC

Sood S., Yu L., Visvanathan K., Angus P. W., Gow P. J., Testro A. G. Immune function biomarker QuantiFERON-Monitor is associated with infection risk in cirrhotic patients. World Journal of Hepatology . 2016;8(35):1569–1575. doi: 10.4254/wjh.v8.i35.1569. PubMed DOI PMC

Willis M. A., Cohen J. A. Fingolimod therapy for multiple sclerosis. Seminars in Neurology . 2013;33(1):37–44. doi: 10.1055/s-0033-1343794. PubMed DOI

Thompson A. J., Banwell B. L., Barkhof F., et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology . 2018;17(2):162–173. doi: 10.1016/S1474-4422(17)30470-2. PubMed DOI

Lublin F. D., Reingold S. C., National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis Defining the clinical course of multiple sclerosis: results of an international survey. Neurology . 1996;46(4):907–911. doi: 10.1212/WNL.46.4.907. PubMed DOI

Lublin F. D., Reingold S. C., Cohen J. A., et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology . 2014;83(3):278–286. doi: 10.1212/WNL.0000000000000560. PubMed DOI PMC

R Core Team. Vienna: R Foundation for Statistical Computing; 2018. R: A Language and Environment for Statistical Computing. https://www.R-project.org .

Ottenlinger F., Schwiebs A., Pfarr K., et al. Fingolimod targeting protein phosphatase 2A differently affects IL-33 induced IL-2 and IFN-γ production in CD8+ lymphocytes. European Journal of Immunology . 2016;46(4):941–951. doi: 10.1002/eji.201545805. PubMed DOI

Bobnar S. T., Stenovec M., Miš K., Pirkmajer S., Zorec R. Fingolimod suppresses the proinflammatory status of interferon-γ-activated cultured rat astrocytes. Molecular Neurobiology . 2019;56:5971–5986. doi: 10.1007/s12035-019-1481-x. PubMed DOI

Eken A., Yetkin M. F., Vural A., et al. Fingolimod alters tissue distribution and cytokine production of human and murine innate lymphoid cells. Frontiers in Immunology . 2019;10 doi: 10.3389/fimmu.2019.00217.217 PubMed DOI PMC

Yang T., Tian X., Chen C.-Y., et al. The efficacy and safety of fingolimod in patients with relapsing multiple sclerosis: a meta-analysis. British Journal of Clinical Pharmacology . 2020;86(4):637–645. doi: 10.1111/bcp.14198. PubMed DOI PMC

Haas J., Jeffery D., Silva D., et al. Early initiation of fingolimod reduces the rate of severe relapses over the long term: post hoc analysis from the FREEDOMS, FREEDOMS II, and TRANSFORMS studies. Multiple Sclerosis and Related Disorders . 2019;36 doi: 10.1016/j.msard.2019.07.011.101335 PubMed DOI

Huwiler A., Zangemeister-Wittke U. The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: recent findings and new perspectives. Pharmacology & Therapeutics . 2018;185:34–49. doi: 10.1016/j.pharmthera.2017.11.001. PubMed DOI

Hjorth M., Dandu N., Mellergård J. Treatment effects of fingolimod in multiple sclerosis: selective changes in peripheral blood lymphocyte subsets. PLOS ONE . 2020;15(2) doi: 10.1371/journal.pone.0228380.e0228380 PubMed DOI PMC

Olsson T. Cytokines in neuroinflammatory disease: role of myelin autoreactive T cell production of interferon-gamma. Journal of Neuroimmunology . 1992;40(2-3):211–218. doi: 10.1016/0165-5728(92)90135-8. PubMed DOI

Dettke M., Scheidt P., Prange H., Kirchner H. Correlation between interferon production and clinical disease activity in patients with multiple sclerosis. Journal of Clinical Immunology . 1997;17:293–300. doi: 10.1023/A:1027374615106. PubMed DOI

Aloisi F., Ria F., Adorini L., Aloisi F., Ria F., Adorini L. Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes. Immunology Today . 2000;21(3):141–147. doi: 10.1016/S0167-5699(99)01512-1. PubMed DOI

Popko B., Baerwald K. D. Oligodendroglial response to the immune cytokine interferon gamma. Neurochemical Research . 1999;24:331–338. doi: 10.1023/A:1022586726510. PubMed DOI

Frisullo G., Nociti V., Iorio R., et al. IL17 and IFNγ production by peripheral blood mononuclear cells from clinically isolated syndrome to secondary progressive multiple sclerosis. Cytokine . 2008;44(1):22–25. doi: 10.1016/j.cyto.2008.08.007. PubMed DOI

Quantiferon Monitor Testing Sheds Light on Immune System Disparities between Multiple Sclerosis Patients and Healthy Individuals