Per haps RTL may modulate the pathophysiological role that platelets play in neurodegenerative diseases such as MS. A number of platelet ligands and pathways have been identified that negatively regulate platelet function. For instance, recent studies have shown negative regulatory roles ZD1839 for the platelet ligands semaphorin Inhibitors,Modulators,Libraries 3A, his tone H1, thrombospondin 1, and low density lipoprotein. Our current study provides evidence that RTL, in addition to serving as a platelet ligand, may serve to negatively regulate agonist induced platelet function, as evidenced by the fact that RTL down regu lated platelet aggregation to collagen. Moreover, our study provides evidence that RTL inhibits occlusive thrombus formation on collagen coated surfaces under physiologically relevant pressure gradients.
Among various platelet surface RTL receptors, one potential candidate we identified was CD40, a Inhibitors,Modulators,Libraries co stimu latory molecule that regulates lymphocyte signaling upon antigen presentation. CD40 is known Inhibitors,Modulators,Libraries to contribute to the initiation, activation, and amplification of immune responses. CD40 CD40 ligand interactions are well described in MS, as CD40L T cells are known to be greatly increased in MS patients. Moreover, CD40 is expressed on platelets and APCs, but not T cells, in accord with the peripheral blood populations we have shown to bind RTL. We therefore tested the hypothesis that CD40 was the plate let receptor for RTL. Our preliminary findings demon strated that purified platelets from CD40 mice bind to RTL at the same level as compared to platelets from wild type mice, arguing against a role Inhibitors,Modulators,Libraries for CD40 as an RTL receptor on mouse platelets.
Our future efforts will be focused on identifying the putative RTL receptor on peripheral blood platelets. The characterization of the molecular mechanisms by which RTL binds to peri pheral blood Inhibitors,Modulators,Libraries cells may better the understanding of the pharmacokinetics of RTL drug delivery as well as the further development of RTL for therapy in autoimmune diseases. Background Persistent demyelination often follows recurrent inflam mation in multiple sclerosis, even though oligo dendroglial progenitor cells are present in the adult CNS as a potential source of oligodendrocytes for remyelination after loss of myelin.
As a pathologi cal mechanism underlying this remyelination failure, accumulating evidence indicates that interferon g, the only type II IFN secreted into the lesions by infil trating T helper 1 cells and natural killer cells, induces cytotoxic effects on OPCs, and inhibits their dif ferentiation, selleck chem leading to failure in de novo myelination by OPCs. We also demonstrated in our previous study that actively proliferating OPCs are far more sus ceptible to cytotoxic effects of IFNg than are post mitotic mature myelinating oligodendrocytes.