Endothelial basement membrane laminin [alpha]5 selectively inhibits T lymphocyte extravasation into the brain

Specific inhibition of the entry of encephalitogenic T lymphocytes into the central nervous system in multiple sclerosis would provide a means of inhibiting disease without compromising innate immune responses. We show here that targeting lymphocyte interactions with endothelial basement membrane laminins provides such a possibility. In mouse experimental autoimmune encephalomyelitis, T lymphocyte extravasation correlates with sites expressing laminin [alpha]4 and small amounts of laminin [alpha]5. In mice lacking laminin [alpha]4, laminin [alpha]5 is ubiquitously expressed along the vascular tree, resulting in marked and selective reduction of T lymphocyte infiltration into the brain and reduced disease susceptibility and severity. Vessel phenotype and immune response were not affected in these mice. Rather, laminin [alpha]5 directly inhibited integrin [alpha].sub.6][beta].sub.1] migration of T lymphocytes through laminin [alpha]4. The data indicate that T lymphocytes use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier, permitting specific targeting of this immune cell population.
During leukocyte extravasation into inflamed tissues, cells quickly traverse the endothelial cell monolayer where they subsequently face the endothelial basement membrane. Previous data has shown that although Leukocyte transmigration of [...]