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NEUROLOGY 2008;71:1261-1267
© 2008 American Academy of Neurology

FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis

M. Mehling, MD, V. Brinkmann, PhD, J. Antel, MD, A. Bar-Or, MD, N. Goebels, MD, C. Vedrine, C. Kristofic, J. Kuhle, MD, R.L.P. Lindberg, PhD and L. Kappos, MD

From the Departments of Biomedicine and Neurology (M.M., J.K., R.L.P.L., L.K.), University Hospital, Basel; Department of Autoimmunity, Transplantation & Inflammation (V.B., C.V., C.K.), Novartis Institutes for BioMedical Research, Basel, Switzerland; Montreal Neurological Institute (J.A., A.B.-O.), McGill University, Montreal, Canada; and Department of Neurology (N.G.), University Hospital, Zürich, Switzerland.

Address correspondence and reprint requests to Professor Ludwig Kappos, Departments of Biomedicine and Neurology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland lkappos{at}uhbs.ch

Background: The oral immunomodulator FTY720 has shown efficacy in patients with relapsing multiple sclerosis (MS). FTY720 functionally antagonizes sphingosine 1-phosphate receptor-1 (S1P1) on T cells and consequently inhibits S1P/S1P1-dependent lymphocyte egress from secondary lymphoid organs. Little is known about the phenotype and function of T cells remaining in peripheral blood during long-term FTY720 treatment.

Methods: T cells from FTY720-treated, interferon-beta (IFNβ)-treated and untreated patients with MS, and healthy donors (HD) were analyzed with respect to T cell subpopulation composition, proliferation, and cytokine production.

Results: In FTY720-treated patients (n = 16), peripheral blood CD4+ and CD8+ T cell counts were reduced by approximately 80% and 60% when compared to the other groups (IFNβ: n = 7; untreated: n = 5; HD: n = 10). This related to selective reduction of naïve (CCR7+CD45RA+) and central memory (CCR7+CD45RA–) T cells (TCM), and resulted in a relative increase of peripheral effector memory (CCR7–CD45RA– [TEM] and CCR7–CD45RA+ [TEMRA]) T cells. The remaining blood T cell populations displayed a reduced potential to secrete IL-2 and to proliferate in vitro, but rapidly produced interferon-gamma upon reactivation, confirming a functional TEM/TEMRA phenotype. Neither FTY720 nor FTY720-P directly suppressed proliferation or cytokine production by T cells.

Conclusion: Therapeutic dosing of FTY720 reduces naïve T cells and TCM, but not TEM, in blood, without affecting T cell function. This is presumably because naïve T cells and TCM express the homing receptor CCR7, allowing recirculation to secondary lymphoid tissues on a regular basis and, thus, trapping of the cells by FTY720 in lymph nodes.

Abbreviations: DC = dendritic cells; HD = healthy donors; IFNβ = interferon-beta; IFN{gamma} = interferon-gamma; IL-2 = interleukin-2; LN = lymph node; mAb = monoclonal antibody; MS = multiple sclerosis; PBMC = peripheral blood mononuclear cells; PE = phycoerythrin; S1P1 = sphingosine 1-phosphate receptor-1; SEB = Staphylococcus enterotoxin B; SLO = secondary lymphatic organs; TCM = central memory T cells; TEM = effector memory T cells.

Supplemental data at www.neurology.org

*These authors contributed equally.

Supported by the Swiss Multiple Sclerosis Society and the Novartis Research Foundation. M. Mehling is supported by the Swiss National Center of Competence in Research (NCCR) "Neural Plasticity and Repair."

Disclosure: V. Brinkmann, C. Vedrine, and C. Kristofic are employees of Novartis AG Basel, Switzerland. The other authors report no disclosures.

Received January 14, 2008. Accepted in final form July 10, 2008.






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