FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis.
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 (IFNbeta)-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 (IFN beta: n = 7; untreated: n = 5; HD: n = 10). This related to selective reduction of naive (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.


CONCLUSIONS
Therapeutic dosing of FTY720 reduces naïve T cells and TCM, but not TEM, in blood, without affecting T cell function. This is presumably because naive 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.
Mehling
M
M
Department of Biomedicine and Neurology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
Brinkmann
V
V
Antel
J
J
Bar-Or
A
A
Goebels
N
N
Vedrine
C
C
Kristofic
C
C
Kuhle
J
J
Lindberg
R L P
RL
Kappos
L
L
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D016131:Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology*; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D015703:Antigens, CD; D016207:Cytokines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011409:Propylene Glycols; D007371:Interferon-gamma; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine