Monitoring Natural Killer Cells in Multiple Sclerosis Patients Treated With Fingolimod
Monitoring Natural Killer Cells in Multiple Sclerosis Patients Treated With Fingolimod
Data on fingolimod effects on NK cells are so far conflicting. A longitudinal study on
 fingolimod treated kidney transplant patients showed that NK cells were not influenced in any
 of the treatment groups. However, more recent reports indicate an increased frequency of NK
 cells in peripheral blood and CSF of MS patients treated with fingolimod and a relative
 reduction of immature CD56bright NK cells in fingolimod-treated MS patients. It has been
 demonstrated that the expression of NK cell relevant sphingosine 1-phosphate (S1P) receptors
 seems to increase during NK cell maturation. Thus, different NK cell sub-types may response
 differently to S1P-receptor agonist such as fingolimod.

 Therefore, the investigators aim to investigate longitudinally (baseline vs. treatment) the
 effects of fingolimod on NK cell maturation/differentiation.
In the past decade, it has become evident that natural killer (NK) cells are more than simply
 killers and seem to be involved in the regulation of autoimmune conditions such as Multiple
 Sclerosis (MS). Yet, the complexity of NK cell activation and maturation is only now being
 understood. Several recent publications have reported on markers characterizing different
 stages of human NK cell maturation/ differentiation, including CD27, CD62L, CD94 and CD57. In
 our more recent study, the investigators demonstrated that the chemokine receptor CX3CR1
 represents an additional marker for NK cells, which in conjunction with other novel markers,
 serves to delineate the sequential stages of human NK cell differentiation. CX3CR1 has been
 suggested to be essential for the protective effects of NK cells in the animal model of MS.
 In this context, the investigators previously reported on the correlation of the frequency of
 circulating CX3CR1-positive NK cells with disease activity in patients with MS. Moreover, our
 unpublished data indicates an association of genetic variation in NK cell-related genes and
 response to IFN-beta treatment. Thus, it appears that NK cells (or at least certain NK cell
 fractions) may be not only protective in MS but also mediators of therapeutic benefits.

 Fingolimod (GILENYA®) is a modulator of the sphingosine 1-phosphate receptor (S1P-receptors)
 indicated for the treatment of patients with relapsing forms of MS to reduce the frequency of
 clinical relapses. Gilenya® is licensed in Germany since April 2011 as an escalation therapy
 for patients with highly active RRMS.

 Data on fingolimod effects on NK cells are so far conflicting. A longitudinal study on
 fingolimod treated kidney transplant patients showed that NK cells were not influenced in any
 of the treatment groups. However, more recent reports indicate an increased frequency of NK
 cells in peripheral blood and CSF of MS patients treated with fingolimod and a relative
 reduction of immature CD56bright NK cells in fingolimod-treated MS patients. However, this
 latter study exclusively compared frequencies of NK cells in untreated MS patients and
 patients treated with fingolimod, while longitudinal intraindividual data during treatment
 was not presented.

 Moreover, these two studies have not considered the potential diverse effects of fingolimod
 on different NK cells subpopulations. It has been demonstrated that the expression of NK cell
 relevant sphingosine 1-phosphate (S1P) receptors seems to increase during NK cell maturation.
 Thus, different NK cell sub-types may response differently to S1P-receptor agonist such as
 fingolimod.

 Therefore, the investigators aim to investigate longitudinally (baseline vs. treatment) the
 effects of fingolimod on NK cell maturation/differentiation.
Inclusion Criteria:

 -  Definite diagnosis of RRMS according to the 2010 revised McDonald criteria (Polman et
 al., 2011)

 -  18 to 64 years old

 -  Indication for on-label treatment with fingolimod (Gilenya®) ac-cording to the current
 approval

 -  EDSS score ≤ 6,0

 -  Neurological stable with no evidence of relapse or corticosteroid treatment within 30
 days prior to screening

 -  Ability to provide written informed consent

 -  Highly effective contraception (Pearl Index < 1), reliable abstinence from any
 heterosexual relationships, or sterilization of the only partner in women of
 childbearing potential

 -  Negative pregnancy test (HCG rapid test in the urine) at screening and baseline in
 women of childbearing potential

 Exclusion Criteria:

 -  Patients with MS manifestations other than RRMS

 -  Patients with known contraindications to Gilenya® according to the current
 "Fachinformation", in particular

 -  Immunodeficiency syndrome

 -  Increased risk of opportunistic infections

 -  Severe active or chronic active infections (hepatitis, tuberculosis)

 -  History or presence of malignancy (other than localized basal or squamous cell
 carcinoma of the skin). Severe liver dysfunction (Child Pugh C)

 -  Hypersensitivity against active or any other compound of study medication

 -  2nd degree Mobitz Type II or higher degree AV block, Sick-sinus syndrome, or
 Sinuatrial heart block, Significant QT prolongation (QTc>470 msec (female) or >450
 msec (males))

 -  History of symptomatic bradycardia or recurrent syncope, known ischaemic heart
 disease, cerebrovascular disease, history of myocardial infarction, hypokalaemia,
 congestive heart failure, history of cardiac arrest, uncontrolled hypertension, or
 severe sleep apnea. Patients with clinically significant liver, kidney or bone marrow
 dysfunction, defined by the following laboratory values at the time of screening:

 -  HB <8.5 g / dl

 -  WBC <2.5 / nl

 -  platelets <100/nl

 -  creatinine clearance by Cockroft-Gault formula: Cl <110ml/min (men) and Cl <95ml/min
 (women), from age of 30 limit drops 10ml/min per decade

 -  AST / ALT> 3.5 times higher than the upper reference value

 -  bilirubin > 2.0 mg / dl

 -  Patients without a history of varicella or without vaccination against varicella
 zoster virus (VZV) and VZV negative antibody serology

 -  Pregnancy or lactation

 -  Participation in another interventional clinical trial within the last 3 months prior
 to baseline or during the study period

 -  Treatment with Natalizumab within the last 3 months prior to baseline, treatment with
 mitoxantrone, azathioprine or any other immunosuppressive drugs except prednisolone
 within the last 6 months prior to baseline.

 -  Patients receiving antiarrythmics class Ia (e.g. quinidine, disopyramide) or class III
 (e.g. amiodarone, sotalol) or beta blockers. Patients receiving heart rate lowering
 calcium channel blockers (e.g. verapamil, diltiazem or ivabradine) or other
 sub-stances which may decrease heart rate (e.g. digoxin, anticholinesteratic agents or
 pilocarpine).

 -  Medical, psychiatric or other conditions that limit the patient' s ability to
 understand the patient's information, to give informed consent or to follow the study
 protocol

 -  Lack of consent to the storage and analysis of pseudonymous data in the context of the
 clinical trial

 -  Prisoners or patients that are housed in an judicial institution