Short communicationInhibition of experimental autoimmune encephalomyelitis by a novel small molecular weight proinflammatory cytokine suppressing drug
Introduction
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated demyelinating disease of the central nervous system (CNS) that serves as a model for multiple sclerosis (MS) (Steinman and Zamvil, 2006). In addition to the requirement for autoreactive T cells, macrophages have been shown to be necessary for EAE development (Brosnan et al., 1981, Cua et al., 1995).
Many chemokines are expressed in the CNS of mice that develop EAE (Godiska et al., 1995). Deletion or neutralization of CCL2 (Huang et al., 2001, Kennedy et al., 1998) as well as deletion of its receptor, CCR2 (Fife et al., 2000) decreased EAE severity. CCL2 (McManus et al., 1998) has been suggested to be involved in MS. Chemokines have been postulated to regulate accumulation of inflammatory cells in the CNS during EAE/MS pathogenesis (Karpus and Ransohoff, 1998).
The development of therapeutics for MS has recently focused on preventing or reducing CNS accumulation of inflammatory cells. Anti-CD49d antibody treatment of mice had a dramatic effect of preventing accumulation of inflammatory cells in the CNS (Yednock et al., 1992). In fact, the ability of Tysabri® to dramatically improve disability in MS patients (Rice et al., 2005) underscores the desirability of this approach. To that end we investigated a novel compound, Minozac (Mzc) (Hu et al., 2007), for its ability to prevent accumulation of inflammatory cells in the CNS and inhibit EAE.
Section snippets
Mice
Female SJL (H2s) mice were purchased from Harlan Sprague Dawley (Indianapolis, IN) and used as previously described (Karpus et al., 1995). Animal care and use was in accordance with the Northwestern University Animal Care and Use Committee and United States Public Health Service policies.
Antigen and antibodies
PLP139-151 (HSLGKWLGHPDKF) was purchased from Peptides International (Louisville, KY) (Karpus et al., 1995). Fluorochrome-conjugated monoclonal antibodies to murine CD4 (RM4-5), CD8a (Ly-2), CD45 (Ly-5), CD11b
Mzc treatment decreased incidence and severity of EAE
Mzc is a recently developed novel suppressor of proinflammatory cytokine production that is water soluble and stable, has a brain:blood peak concentration ratio of 1.5, and is efficacious in an Alzheimer's disease model (Hu et al., 2007). We reasoned that there was significant glia-derived cytokine expression in EAE and asked whether Mzc treatment would have an effect on disease development and progression. Two groups of 12 mice were immunized with PLP139-151 in CFA and monitored for the
Acknowledgments
This work was supported by NS34510, AG028561, NS047586, and AG000260.
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