Regulation of cellular and molecular trafficking across human brain endothelial cells by Th1- and Th2-polarized lymphocytes.

We used adult human brain-derived endothelial cells (HBECs) to model migration of peripheral blood lymphocytes across the blood brain barrier (BBB) as occurs in MS. We demonstrate that enhanced expression of adhesion molecule ICAM-1 and production of chemokines CXCL10/IP-10, CCL2/MCP-1, and CXCL8/IL-8 by HBECs induced by supernatants derived from allogeneic or myelin basic protein-reactive Th1 cells is only partially reversed with anti-IFNgamma antibody. This effect is not reproduced with IFNgamma or TNFalpha alone, implicating the interaction of multiple factors in the overall functional response. Supernatants from Th2 cells neither suppressed nor amplified Th1-induced effects. Although both Th1 and Th2 supernatants modulated the expression and localization of tight junction molecules zonula occludens (ZO)-1 and ZO-2, neither supernatant altered the permeability of HBEC monolayers to albumin or increased subsequent T cell migration rates. Prior migration of Th1 or Th2 cells across HBECs did enhance subsequent passage of cells and soluble molecules. Our results suggest that initial infiltration of either Th1 or Th2 polarized lymphocytes across the BBB contributes to the continuation of an inflammatory response in the central nervous system.