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We investigated the effect of blockade of the lymphotoxin-beta receptor (LTBR) pathway on lacrimal-gland pathology in the NOD mouse model of Sj\u00f6gren's syndrome.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods\n<\/jats:title>\n                        <jats:p>Male NOD mice were treated for up to ten weeks with an antagonist, LTBR-Ig, or control mouse antibody MOPC-21. Extra-orbital lacrimal glands were analyzed by immunohistochemistry for high endothelial venules (HEV), by Affymetrix gene-array analysis and real-time PCR for differential gene expression, and by ELISA for CXCL13 protein. Leukocytes from lacrimal glands were analyzed by flow-cytometry. Tear-fluid secretion-rates were measured and the integrity of the ocular surface was scored using slit-lamp microscopy and fluorescein isothiocyanate (FITC) staining. The chemokine CXCL13 was measured by ELISA in sera from Sj\u00f6gren's syndrome patients (<jats:italic>n<\/jats:italic> = 27) and healthy controls (<jats:italic>n<\/jats:italic> = 30). Statistical analysis was by the two-tailed, unpaired T-test, or the Mann-Whitney-test for ocular integrity scores.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results\n<\/jats:title>\n                        <jats:p>LTBR blockade for eight weeks reduced B-cell accumulation (approximately 5-fold), eliminated HEV in lacrimal glands, and reduced the entry rate of lymphocytes into lacrimal glands. Affymetrix-chip analysis revealed numerous changes in mRNA expression due to LTBR blockade, including reduction of homeostatic chemokine expression. The reduction of <jats:italic>CXCL13, CCL21, CCL19<\/jats:italic> mRNA and the HEV-associated gene <jats:italic>GLYCAM-1<\/jats:italic> was confirmed by PCR analysis. CXCL13 protein increased with disease progression in lacrimal-gland homogenates, but after LTBR blockade for 8 weeks, CXCL13 was reduced approximately 6-fold to 8.4 pg\/mg (+\/- 2.7) from 51 pg\/mg (+\/-5.3) in lacrimal glands of 16 week old control mice. Mice given LTBR blockade exhibited an approximately two-fold greater tear-fluid secretion than control mice (<jats:italic>P<\/jats:italic> = 0.001), and had a significantly improved ocular surface integrity score (<jats:italic>P<\/jats:italic> = 0.005). The mean CXCL13 concentration in sera from Sj\u00f6gren's patients (<jats:italic>n<\/jats:italic> = 27) was 170 pg\/ml, compared to 92.0 pg\/ml for sera from (<jats:italic>n<\/jats:italic> = 30) healthy controls (<jats:italic>P<\/jats:italic> = 0.01).<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions\n<\/jats:title>\n                        <jats:p>Blockade of LTBR pathways may have therapeutic potential for treatment of Sj\u00f6gren's syndrome.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/ar3507","type":"journal-article","created":{"date-parts":[[2011,12,7]],"date-time":"2011-12-07T21:20:38Z","timestamp":1323292838000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sj\u00f6gren's syndrome"],"prefix":"10.1186","volume":"13","author":[{"given":"Roy A","family":"Fava","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheryl G","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne I","family":"Bolstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadwiga","family":"Bienkowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Papandile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clio P","family":"Mavragani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Gatumu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrine","family":"Skarstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L","family":"Browning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,11,1]]},"reference":[{"key":"3257_CR1","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.1002\/art.21062","volume":"52","author":"F Barone","year":"2005","unstructured":"Barone F, Bombardieri M, Manzo A, Blades MC, Morgan PR, Challacombe SJ, Valesini G, Pitzalis C: Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjogren's syndrome. 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