Effects of Ozanimod on Immune-mediated Mechanisms of Neurodegeneration in Multiple Sclerosis - a Preclinical Study

This is a prospective non interventional study including patients with Relapsing-Remitting Multiple Sclerosis (RRMS) or with Neuromyelitis Optica Spectrum Disorders (NMOSD) and healthy subjects, who are enrolled within the routinely programmed clinical examinations at the IRCCS Neuromed (Pozzilli, Italy), IRCCS Polyclinic Hospital San Martino (Genoa, Italy) and Sant'Andrea Hospital - University of Rome La Sapienza (Rome, Italy). Specifically, the study investigates how ozanimod may contrast neurodegenerative mechanisms triggered by both arms of the adaptive immune response (T and B cells) and by their suboptimal regulation in MS. Overall, the project aims at assessing by in vitro experiments (there will be no patients on treatment with ozanimod and the drug will be only used in vitro): AIM1: ozanimod ability to modulate the synaptotoxic effect of T-cells derived from patients with MS relapse in a MS-chimeric ex-vivo model and to identify possible mediators (IRCCS Neuromed-Pozzilli, in collaboration with Synaptic Immunopathology Laboratory Dep. Systems Medicine, Tor Vergata University of Rome); AIM2: ozanimod ability to reduce the cytokine-mediated breakdown of the BBB and the migration of the here studied immune cells through ex vivo models of BBB (IRCCS Polyclinic Hospital San Martino); AIM3: ozanimod ability to affect the migration properties of Epstein Barr virus (EBV) infected B cells in MS (Sant'Andrea Hospital); AIM4: ozanimod ability to modulate the number and/or function of regulatory T cells (Treg), a lymphocyte population playing a key role in the control of pathogenic adaptive immune responses (Treg Cell Laboratory, Università degli Studi di Napoli "Federico II", Naples, Italy, receiving blood samples from Neuromed Hospital and Sant'Andrea Hospital; not recruiting unit). The work of the four labs is conceptually and operationally integrated: the labs at IRCCS Neuromed-Pozzilli/Tor Vergata University (Aim1) and at Polyclinic Hospital San Martino (Aim2) will investigate the effects of ozanimod on well-known mechanisms of damage in MS, inflammatory synaptopathy and BBB damage and immune cell migration. The lab at Sant'Andrea Hospital (Aim3), will verify whether B cells infected by different EBV genotypes are involved in BBB migration, and how ozanimod may interfere with this mechanism. The Treg Cell Laboratory (Aim4) will investigate whether ozanimod can also act "upstream" of these mechanisms by regulating the adaptive immune response.

Sex

All

Minimum age

18 Years

Maximum age

55 Years

Inclusion Criteria:

Main inclusion criteria of patients with RRMS:

* Relapsing-remitting MS, as diagnosed by the revised 2010 McDonald Criteria
* EDSS score ≤ 5.5;
* Age between 18 and 55 years (exclusive);
* No disease modifying therapies for at least 3 months or treatment naïve;
* No corticosteroid administration in the previous month;
* Disease duration \<10 years;
* Ability to provide written informed consent.

For the estimation of radiological variables, brain and spinal cord MRI will be performed according to clinical practice and lesions will be classified as symptomatic or asymptomatic if they were associated with clinical relapse or not.

Patient groups will be matched by gender, age, ethnicity and MS duration.

Main inclusion criteria of patients with NMOSD (Wingerchuk et al., 2015):

* Positive test for Aquaporin 4 IgG;
* Age between 18 and 55 years (exclusive);
* no immunosuppressive therapies for at least 3 months or treatment naïve
* no corticosteroid administration in the previous month
* disease duration \<10 years
* Ability to provide written informed consent

Healthy subjects

* Age between 18 and 55 years (exclusive), matched by gender, age and ethnicity towards the MS groups.
* Ability to provide written informed consent

Exclusion Criteria:

Exclusion criteria patients with RRMS:

* Adverse effects to MRI imaging with i.v. gadolinium;
* Blood count basal alteration;
* Clinically significant medical condition other than MS, including latent infections (e.g. tuberculosis, viral hepatitis, HIV/AIDS) that might confound the results of the study.

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