Antibody blocking of CLEC12A delays the course and attenuates EAE severity by impairing myeloid cell CNS infiltration: A potential new therapy for multiple sclerosis (CAM4P.158)

Abstract

Abstract The mechanism of dendritic cell (DC) recruitment across the blood brain barrier during neuroinflammation has been the least explored amongst all leukocytes. For cells of myeloid origin, while integrins function at the level of adhesion, the importance of lectins remains unknown. We pursued the study of a highly specific aspect of DC biology, namely the expression of surface C-type lectin receptors (CLRs) for their importance in adherence and transmigration across the blood-brain barrier in response to CCL2 chemotaxis. CLEC12A, an immunoreceptor tyrosine-based inhibitory motif (ITIM) known to recruit Src homology region 2 domain-containing phosphatase (SHP)-1/2, was subsequently identified as one such a target on DCs. SHP-1/2 phosphorylation was further found to facilitate the actin polymerization on DCs that express the WASP Interacting Protein (WIP). To test function of CLEC12A in an animal model of multiple sclerosis (MS), we administered an antibody to block CLEC12A that significantly ameliorated the progression and relapse of experimental autoimmune encephalomyelitis (EAE) in mice through inhibition of demyelination and myeloid cell infiltration into the CNS tissue. Correspondingly, a restoration of DC numbers in the periphery along with decrease in TH17 phenotype within CD4+ T cells was also seen. These studies reveal the utility of a DC-specific mechanism in designing new therapeutics for MS.