Autoimmune responses directed against the central nervous system (CNS) have generally been considered pathogenic in nature. While there are several well understood conditions in which this is the case, there is also a growing body of experimental evidence that both the cellular and humoral immune responses can promote tissue repair following CNS injury and disease. Our laboratory has used various mouse models of demyelinating disease (Theiler's virus, EAE, lysolecithin) to characterize a class of polyreactive IgM autoantibodies that react with oligodendrocyte surface antigens and that promote myelin repair. The purpose of this grant is to evaluate the mechanism by which mouse and human monoclonal antibodies function to promote remyelination via a direct effect on glial cells.
Our specific aims are to: 1. Characterize antibody-induced changes in the local organization of the plasma membrane of oligodendroglia, and to identify the membrane microdomain relevant to antibody-induced signaling. 2. Characterize antibody-induced signaling cascades and identify the second messenger systems relevant to the induction of transcriptional changes involved in oligodendroglial survival, proliferation, and differentiation. 3. Use the lysolecithin model to assess the in vivo effects of treatment with pharmacologic agents (as identified in Aims 1 & 2) on the CNS response to remyelination promoting antibodies. Our findings are expected to provide new insights into the enhancement of remyelination in diseases such as multiple sclerosis. ? ?
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| Perschbacher, Katherine; Smestad, John A; Peters, Justin P et al. (2015) Quantitative PCR analysis of DNA aptamer pharmacokinetics in mice. Nucleic Acid Ther 25:11-9 |
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| Waubant, Emmanuelle; Mowry, Ellen M; Krupp, Lauren et al. (2013) Antibody response to common viruses and human leukocyte antigen-DRB1 in pediatric multiple sclerosis. Mult Scler 19:891-5 |
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| Xu, Xiaohua; Denic, Aleksandar; Warrington, Arthur E et al. (2013) Therapeutics to promote CNS repair: a natural human neuron-binding IgM regulates membrane-raft dynamics and improves motility in a mouse model of multiple sclerosis. J Clin Immunol 33 Suppl 1:S50-6 |
| Watzlawik, Jens O; Warrington, Arthur E; Rodriguez, Moses (2013) PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation. PLoS One 8:e55149 |
| Wootla, Bharath; Denic, Aleksandar; Warrington, Arthur E et al. (2012) Need for a paradigm shift in therapeutic approaches to CNS injury. Expert Rev Neurother 12:409-20 |
| Soldan, M Mateo Paz; Pittock, Sean J; Weigand, Stephen D et al. (2012) Statin therapy and multiple sclerosis disability in a population-based cohort. Mult Scler 18:358-63 |
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