Antibodies to CD44 and integrin α₄, but not L-selectin, prevent central nervous system inflammation and experimental encephalomyelitis by blocking secondary leukocyte recruitment

Abstract

The role of various adhesion molecules in lymphocyte homing to the brain and in inf lammatory autoimmune disease of the central nervous system (CNS) was examined in mice. Activated T cell lines and clones expressed CD44 and integrin ␣ 4 , but not L-selectin, and entered the CNS independent of their antigen specificity. mAbs directed against CD44 and integrin ␣ 4 prevented the transfer of experimental autoimmune encephalomyelitis (EAE) by myelin basic protein-specific T cells. T cells preincubated with anti-CD44 or antiintegrin ␣ 4 were blocked only partially from entering the brain parenchyma. However, both antibodies efficiently prevented CNS inf lammation and clinical expression of EAE when injected in vivo. This effect lasted as long as antibodies were administered. Antibodies specific for Lselectin had no effect on homing of encephalitogenic T cells to the brain or development of EAE. Antiintegrin ␣ 4 and anti-CD44 did not impair the activation and function of encephalitogenic T cells in vitro and did not deplete integrin ␣ 4 -or CD44-positive cells in vivo. These data suggest that, in the absence of leukocyte recruitment, the entry of a reduced number of activated myelin basic protein-reactive T cells in the CNS is not sufficient for the development and expression of EAE. We propose that antibodies to integrin ␣ 4 and CD44 prevent clinical disease by partially targeting the primary inf lux of encephalitogenic T cells and by preventing the secondary inf lux of leukocytes to lesions initiated by the transferred T cells.

Pineal-dependent and -independent effects of photoperiod on immune function in Siberian hamsters (Phodopus sungorus)

“…Among pineal-intact hamsters, paralleling the SD-induced increases in total leukocytes were significant increases in the number of lymphocytes, T cells, and CD62+ leukocytes. Increases in the number of cells expressing CD62 cell surface markersadhesion molecules that participate in the migration of lymphocytes through endothelium during inflammatory responses -together with increases in total T cells, would be predicted to facilitate delayed-type hypersensitivity (DTH) inflammatory responses in SD (Chen et al, 1997;Brocke et al, 1999), as has been reported previously (Bilbo et al, 2002a,b;Prendergast et al, 2004a;. The elimination of photoperiodic enhancement of T cells and CD62+ leukocytes by PINx suggests that SD enhancement of such inflammatory responses would likely be abolished by PINx as well.…”

IFN-β Gene Deletion Leads to Augmented and Chronic Demyelinating Experimental Autoimmune Encephalomyelitis

“…VCAM-1 expression on endothelial cells serves as an adhesion molecule and binds VLA-4-expressing cells, mainly monocytes, macrophages, and activated T cells. Numerous studies have shown the importance of an interaction between VLA-4 ϩ lymphocytes and VCAM-1 ϩ endothelial cells for the development of EAE (33)(34)(35). In this context, down-regulation of VCAM-1 on macrophages could promote VLA-4 ϩ T cell interaction with VCAM-1 ϩ endothelial cells and subsequent transendothelial migration.…”

Cell Therapy for Multiple Sclerosis

“…The specific homing of NSCs to the brain was explained in part by the constitutive expression of a wide array of adhesion molecules (integrins, selectins, and so forth) and chemokine receptors by the transplanted cells [273,275]. Integrins promote selective CNS homing through the interaction between transplanted cells and integrin receptor-expressing activated endothelial and ependymal cells surrounding inflamed brain tissues [276,277]. Specifically, transendothelial migration was related to the expression of very late antigen-4 (VLA-4) and CD44 on NPCs, interacting with vascular cell adhesion molecule-1 (VCAM-1) and hyaluronic acid, respectively [173,278].…”