Thus, a major action of LTBR antagonism was the reduction of the rate of entry of lymphocytes into lacri mal glands probably due http://www.selleckchem.com/products/CAL-101.html to the virtual elimination of HEV that expressed PNAd. The tight association between the presence of HEV and B cell accumulation is consistent with the notion that HEV formation is an early event in TLT formation. However, in diseased lacrimal glands, the lymphoid cell aggregates appear suspended in an intermediate or immature state since they were slow to acquire the micro Inhibitors,Modulators,Libraries architecture of mature TLT, such as well segregated T cell areas and B cell areas with associated FDC networks. This immature state is very apparent when compared to submandibular glands in female NOD mice. The factors that prevent or delay the organization of the lymphocyte aggregates in lacrimal glands are not understood.

However, one striking difference was Inhibitors,Modulators,Libraries a paucity of lymphatic vessels near lymphoid Inhibitors,Modulators,Libraries aggregates of lacrimal Inhibitors,Modulators,Libraries glands compared to the TLT of dis eased submandibular glands in female NOD mice. LYVE 1 immunoreactive lymphatic vessels were abundant near TLT in submandibular glands of female mice, but lympha tic vessels were essentially absent from the perimeter of the large B cell aggregates in diseased lacrimal glands. Lymphatic vessels have been reported to be rela tively scarce in lacrimal glands, which may make any lym phangiogenic response in lacrimal glands less robust than in salivary glands. Lymph angiogenesis is tightly linked to mature Inhibitors,Modulators,Libraries TLT development, as demonstrated in an experimental model of Hashimotos disease in the thyroid where robust lymph angiogenesis was driven primarily by T cells during development of ectopic follicles.

Inter estingly, it is known that B cells exit lymph nodes in part by directly entering lymphatic vessels in the cortex of lymph nodes, a difficulty in exiting lacrimal glands via lymphatic vessels in a similar fashion could contribute to accumulation selleck chemicals of B cells. We speculate that high levels of CXCL13 and the lack of robust lymph angiogenesis in lacrimal glands contribute to limited egress of B cells from glands. A discordance was noted between the modest down modulation of CXCL13 mRNA and the approximately five fold reduction of CXCL13 protein in lacrimal glands after 8 weeks of LTBR Ig treat ment. One possibility is that LTBR Ig treatment affects elements on the extracellular matrix and peri cellular matrix of HEV that retain CXCL13 in the microenviron ment. Interestingly, lacrimal glands contained approxi mately 10 times more CXCL13 mg tissue measured by ELISA than did salivary glands of female NOD mice of comparable age. This was particularly surprising as FDC networks, a known source of CXCL13 production, were abundant in salivary gland TLT but were rare in lacrimal glands.