Therapy with antibodies against CD40L (CD154) and CD44-variant isoforms reduces experimental autoimmune encephalomyelitis induced by a proteolipid protein peptide

Abstract

Interactions between mononuclear cells are required for the formation of inflammatory infiltrates in the CNS and the activation of cellular effector functions provoking demyelination in MS. Membrane-expressed costimulatory molecules are crucial to such interactions. We therefore investigated whether two costimulatory molecules, CD40L (CD154, expressed on activated CD4-possible T cells) and selected CD44-variant isoforms (expressed on activated CD4-positive T cells), are targets for immunotherapy in MS. The model of experimental autoimmune encephalomyelitis (EAE) induced in SJL-mice by immunization with a peptide derived from the proteolipid protein (PLP139-151) was optimized to address these questions. A previous observation that anti-CD40L (CD154) monoclonal antibodies can effectively prevent EAE in this model was confirmed, and extended by demonstrating that CD40 is expressed by cells of the monocytic lineage infiltrating the spinal cord. In vivo treatment with antibody against the standard isoform of CD44 (CD44s or CD44H) did not affect disease burden. In contrast, combined treatment with antibodies against the isoforms CD44v6, v7 and v10, which are thought to be involved in inflammatory processes, reduced the disease burden considerably. In addition, CD44v10-expressing cells were detected in the spinal cord. These data support the idea that CD40-CD40L interactions form a target for immunotherapy of MS, and indicate that cells expressing CD44v6, v7 and/or v10-containing isoforms have such potential as well.

Hyaluronan Anchored to Activated CD44 on Central Nervous System Vascular Endothelial Cells Promotes Lymphocyte Extravasation in Experimental Autoimmune Encephalomyelitis

“…In the context of inflammatory CNS disease, blocking antibodies against CD44 delay EAE onset and decrease disease severity coincident with fewer lymphocytes present in the CNS (22)(23)(24). Similarly, one report found that EAE induced in CD44 Ϫ/Ϫ mice is significantly attenuated (25).…”

“…Rolling-Previous studies utilizing CD44 neutralizing antibodies suggest that CD44 contributes to EAE onset by promoting lymphocyte extravasation (22)(23)(24). A second study suggests that CD44 promotes EAE pathogenesis by regulating lymphocyte phenotypes (25).…”

“…CD44 splice variants 6, 7, and 10 have been implicated in the early initiation of EAE (24). To determine whether these variants could play a role in anchoring HA to ECs, we assayed ECs with and without TNF␣ stimulation for CD44 variant 6, 7, and 10 mRNA expression.…”

“…Ϫ/Ϫ Mice-Inhibition of CD44 activity using neutralizing antibodies (22)(23)(24) or deletion of the CD44 gene (25) are reported to attenuate EAE onset and progression. To confirm that genetic ablation of CD44 is sufficient to ameliorate EAE symptoms, we tested how EAE progresses in CD44 Ϫ/Ϫ mice that develop severe disease.…”

A novel antiapoptotic mechanism based on interference of Fas signaling by CD44 variant isoforms

“…Experimental autoimmune encephalomyelitis and experimental colitis can be efficiently cured by anti-CD44v antibodies. 20,21 The first evidence that the CD44v region might be involved in apoptosis blockade came from studies with mice lacking CD44v6v7. In contrast to the CD44 wild-type mice, these mice were strongly protected against experimental colitis due to increased apoptosis in the inflammatory lesions of the lamina propria.…”