To assess the effect of RTL on platelet function, a solution of purified human platelets was treated with RTL under constant stirring in an aggregometer. Platelet aggregation induced by the platelet agonist, collagen, was inhibited by the http://www.selleckchem.com/products/Dasatinib.html addition of RTL1000. Addition of RTL1000 alone failed to initiate either platelet shape changes or aggregation. We next investigated the effect of RTL on occlusive thrombus formation. Recalcified blood was driven by a constant pressure gradient through collagen coated capillaries at an initial shear rate of 300 s 1, and flow through the capillary was monitored until occlusion. Our data demonstrate that RTL substantially prolonged the time to occlusion. Taken together, these findings provide the first evidence that RTL platelet binding may negatively regulate platelet function and prolong occlu sive thrombus formation.

Discussion Multiple sclerosis is regarded as a prototypical disease state Inhibitors,Modulators,Libraries resultant of neuroinflammation. RTLs have been engineered to augment antigen driven immunosuppres sion of autoreactive T cells by presenting TCR ligands in the absence of co stimulatory Inhibitors,Modulators,Libraries signals that are normally supplemented by antigen presenting cells. RTLs have been shown to reduce T cell driven encephalitogenicity and both clinical and histological signs of EAE. Previous studies suggested that RTLs confer a therapeutic benefit via the downregulation of T cell mediated inflammation and by modifying the permeability of the blood brain barrier in a murine model of EAE or ischemic stroke.

RTLs were found to decrease the levels of systemic chemokines and adhesion molecules on the Inhibitors,Modulators,Libraries CNS endothelium as well as cytokines that switch on anti inflammatory effectors rather than increasing anti body production by B cells. Although RTLs were originally thought to act as a partial agonist via TCR, our recent study demonstrated the inability of sple nic CD3 T cells to bind RTLs. Rather, we found that RTLs bound APC populations including B cells, macro phages, and dendritic cells, in an antigenic independent manner. Perhaps RTL armed splenic APCs suppress the transfer of EAE by antigen stimulated T cells. Alternatively, peripheral Inhibitors,Modulators,Libraries blood cells may bind RTL through an unknown surface receptor distinct from TCR, indirectly inducing T cell tolerance against self antigen.

Our study was designed to determine whether peripheral blood cell populations, Inhibitors,Modulators,Libraries such as platelets, can bind to RTL, thus offering a level of redundancy to APCs. Platelets, well known regulators of hemostasis and thrombosis, have been implicated in playing an essen tial role in inflammation and immunity. Activated platelets shed granules and microparticles which con tain a variety of adhesive molecules and immunomo dulatory factors, resulting in the localized recruitment chronic myelocytic leukemia of immune cells under shear. Abnormal platelet activa tion has been documented in MS patients.