In the male NOD mouse, within the first 6 weeks of age lacri mal glands undergo markedly altered http://www.selleckchem.com/products/pazopanib.html gene Inhibitors,Modulators,Libraries expression, including elevated expression of cathepsin, increased extra cellular matrix degradation and altered lipid homeostasis. These changes precede the massive accumulation of leukocytes that culminates in overt exocrinopathy by 12 to 16 weeks of age. In this study, differential gene expression analysis with Affy metrix gene arrays showed that antagonism of the LTBR axis altered the expression of a wide variety of genes related to lymphocyte trafficking, lymphocyte function and lacrimal gland function, and these changes coincided with improvement in tear fluid secretion and ocular integrity, two measures of overall ocular health.

While the precise mechanism of action are not yet clear, the Inhibitors,Modulators,Libraries net result of LTBR antagonism was a diminution of the loss of tear production by lacrimal glands and partial pro tection from loss of the integrity of the ocular surface. The beneficial effects of LTBR antagonism reported here are likely linked to diverse factors. It is the com bined effect of reduced tear fluid volume and the altered composition of tear fluid due to lacrimal gland disease that results in damage to the epithelial cell layer of the ocular surface. The reduced delivery of protective anti bodies and of growth factors such as epidermal growth factor and nerve growth factor, which have been implicated in corneal epithelial homeostasis, are thought to contribute to loss of ocular surface integ rity. Administration of LTBR Ig spared some of these protein factors of tear fluid from disease driven down regulation.

For example, LTBR Ig treatment diminished the disease associated losses in mRNA Inhibitors,Modulators,Libraries expression of NGF, EGF, mucin 10 and EGF binding protein and may have helped to maintain the integrity of the ocular surface, as these Inhibitors,Modulators,Libraries proteins may have roles in cor neal epithelial cell renewal. Increased repair Inhibitors,Modulators,Libraries of the ocular surface and the gland itself may be factors in the beneficial outcome of LTBR blockade. Future studies are planned to evaluate this possibility more directly. The gene expression patterns we observed by Affyme trix chip assay clearly reflected the profound reduction in the number of leukocytes in lacrimal glands after antagonism of the LTBR axis for 8 weeks. Many genes related to B cell signaling pathways that are elevated by disease progression were reduced by LTBR Ig treat ments.

The ability of LTBR Ig to prevent and reverse the differentiation of venules near the leukocyte infiltrates to HEV was also reflected in the gene expression data, with Glycam1 and Chst4 being profoundly Brefeldin A FDA reduced, resulting in a co ordinate reduction of L selection expression, probably because of reduced entry of na ve lymphocytes into lacrimal glands.