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CD44 is involved in selective leucocyte extravasation during inflammatory central nervous system disease
F R Brennan1, J K O'Neill, S J Allen
1Rheumatic Diseases Unit, Western General Hospital, Edinburgh, UK.
Insights
This study reveals CD44
Area of Science:
- Neuroimmunology
- Cellular Immunology
Background:
- Experimental autoimmune encephalomyelitis (EAE) involves CD4+ memory T cell recruitment to the central nervous system (CNS).
- CD44 expression on these cells is dynamic during CNS infiltration.
Purpose of the Study:
- To investigate the role of CD44 in T cell extravasation into the CNS during EAE.
- To evaluate CD44 as a therapeutic target for T-cell-mediated inflammatory diseases.
Main Methods:
- Administration of CD44-specific antibody (IM7.8.1) in a murine EAE model.
- Assessment of mononuclear cell infiltration into the CNS.
- Comparison with antibody targeting very late activation antigen-4 (VLA-4).
Main Results:
- CD44 antibody treatment induced CD44 shedding, prevented EAE development, and reduced severity by inhibiting CNS mononuclear cell infiltration.
- Lymph node trafficking of naive cells was unaffected by CD44 antibody.
- VLA-4 antibody inhibited homing to both CNS and lymph nodes.
Conclusions:
- CD44 plays a crucial role in T cell homing to the CNS during EAE.
- CD44 is implicated in lymphocyte trafficking to inflammatory sites.
- CD44 represents a potential therapeutic target for T-cell-mediated inflammatory conditions like multiple sclerosis.
Abstract:
Clinical signs of experimental autoimmune encephalomyelitis (EAE) are associated with the selective recruitment of CD4+ memory (CD45RBlow CD44high) T cells into the central nervous system (CNS). However, we have found that many of these recently recruited memory cells are CD44low, suggesting that the CD44 antigen may be involved in, and transiently lost during, the extravasation process. Indeed, administration of a CD44-specific antibody (IM7.8.1) induced leucocyte CD44 shedding and both prevented the development and ameliorated the severity of established EAE by inhibiting mononuclear cell infiltration into the CNS. Trafficking of cells into lymph nodes, however, a property mainly of naïve cells, was essentially unaffected. In contrast, treatment with antibody to very late activation antigen-4 (VLA-4) prevented homing to both the CNS and to lymph nodes. This study contests previous reports that dismissed a role for CD44 in inflammation of the CNS and, coupled with observations in murine dermatitis and arthritis, suggests that CD44 is involved in the homing of primed lymphocytes to sites of inflammation. CD44 should therefore be considered a target for immunotherapy of T-cell-mediated inflammatory diseases, such as multiple sclerosis.