Tuesday, 4 September 2012

Research: yet another action of S1P1 agonists

Galicia-Rosas G, Pikor N, Schwartz JA, Rojas O, Jian A, Summers-Deluca L, Ostrowski M, Nuesslein-Hildesheim B, Gommerman JL.A Sphingosine-1-Phosphate Receptor 1-Directed Agonist Reduces Central Nervous System Inflammation in a Plasmacytoid Dendritic Cell-Dependent Manner.J Immunol. 2012 Aug 29. [Epub ahead of print]

Gradients of the sphingolipid sphingosine-1-phosphate (S1P) are responsible for the egress of lymphocytes from lymph nodes by activating the S1P1 receptor expressed on the surface of lymphocytes. Small molecule drugs that downregulate S1P receptors induce the sequestration of lymphocytes within lymph nodes, thus preventing lymphocytes from accessing sites of inflammation. In particular, FTY720 (= Fingolimod = Gilenya), a pan-S1P receptor agonist, has been efficacious in the treatment of multiple sclerosis as well as its animal model, experimental autoimmune encephalomyelitis (EAE), by virtue of its ability to restrain lymphocytes within the lymph nodes, thus precluding their migration into the CNS. 

However, multiple leucocyte subsets express S1P receptors of varying types, and although it is beneficial to prevent transmigration of pro inflammatory lymphocytes into the CNS, allowing access of regulatory leucocyte subsets to the CNS is desirable. In this study, we show that an S1P1-specific agonist (AUY954) is clinically efficacious in ameliorating pre-established EAE in SJL/J mice. Efficacy of AUY954 correlated with a reduction of lymphocytes in the CNS, but access of plasmacytoid dendritic cells (pDCs) to the CNS was unimpaired, and the presence of pDCs was found to be an important cofactor in mediating the clinical efficacy of AUY954. These results indicate that pDCs are important in quieting autoimmune responses during EAE, and that trafficking inhibitors that are permissive for pDC accumulation in the CNS may be of therapeutic value for the treatment of multiple sclerosis.
                                                                    S1P1 receptor

This study suggests that plasmacytoid cells, which are immune cells that circulate in the blood and are found in peripheral lymphoid organs, are not affected by relatively S1P1 receptor specific agonists. Gilenya hits 4/5 S1P1 receptors and so does more.  Gilenya works by white blood cells from getting out of lymph nodes and so they cannot get to the brain. We have also heard from previous posts that there can be effects on the blood brain barrier too. So in this study they find that S1P1 agonists block white blood cells from getting in the CNS, but do not inhibit dendritic cells from entering the CNS and it is they that have a part to play in the inhibition of at least AUY954.

Why would dendritic cells enter the CNS if there were no T cells first getting into the CNS to kick off disease?
 
You may be interested to know that BAF-312 (S1P1/S1P5 agonist) is in clinical development.

CoI: None Really but Team G has support from Novartis the makers of Gilenya

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