| Popis: |
The immunomodulatory drug FTY720 is presently approved for the treatment of relapsing remitting multiple sclerosis. It is a prodrug that requires activation by sphingosine kinase 2 (SK 2) to induce T cell homing to secondary lymphoid tissue. In this study we have investigated the role of SK 2 in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. We show that SK 2 deficiency reduced clinical symptoms of EAE. Furthermore in SK 2 deficient mice the protective effect of FTY720 on EAE was abolished while the non prodrug FTY720 derivative ST 968 was still fully active. Protection was paralleled by reduced numbers of T lymphocytes in blood and a reduced blood brain barrier leakage. This correlated with reduced mRNA expression of ICAM 1 VCAM 1 but enhanced expression of PECAM 1. A similar regulation of permeability and of PECAM 1 was seen in primary cultures of isolated mouse brain vascular endothelial cells and in a human immortalized cell line upon SK 2 knockdown. In summary these data demonstrated that deletion of SK 2 exerts a protective effect on the pathogenesis of EAE in C57BL/6 mice and that SK 2 is essential for the protective effect of FTY720 but not of ST 968. Thus ST 968 is a promising novel immunomodulatory compound that may be a valuable alternative to FTY720 under conditions where SK 2 activity is limited |
