Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory demyelinating disease of the CNS that serves as a model for human multiple sclerosis (MS). A relapsing-remitting form of EAE (R-EAE) is induced in SJL/J mice following active immunization with either the major encephalitogenic determinants of proteolipid protein (PLP 139-151) or myelin basic protein (MBP84-104) or by the adoptive transfer of peptide-specific T cells. During the previous funding period we have made the critical observation that disease progression (relapses) in this peptide-induced R-EAE models are due primarily to the recruitment of T cell responses against non-cross reactive endogenous myelin epitopes on the same or different myelin proteins (intramolecular or intermolecular epitope spreading). Since numerous human autoimmune diseases (e.g., MS, rheumatoid arthritis, SLE) display relapsing-remitting or chronic- progressive courses, epitope spreading has very important implication for the pathogenesis for these human diseases and for the potential application of specific forms of immunotherapy to their treatment. We propose to continue to test the hypothesis that immune responses to endogenous myelin epitopes play the predominant role in progression of R- EAE and that these T cells are primed as a result of exposure to myelin epitopes released during acute CNS damage. The myelin epitope specificity, precursor frequency, receptor repertoire, cytokine (Th1/Th2) profile, and encephalitogenic potential of peripheral (Specific Aim 1) and CNS-resident (Specific Aim 2) CD4+ T cells at varying stages of the R-EAE disease process will be assessed.
Specific Aim 3 will determine the underlying mechanisms behind the temporal progression of immune responses to the various myelin epitopes in the peptide-induced EAE models by assessing the T cell precursor frequency, MHC class II binding affinity, and efficiency of processing of encephalitogenic myelin epitopes on PLP, MBP, MOG, and MAG. In addition, the relative ability of various potential CNS-resident APCs (astrocytes, microglia, infiltrating macrophages, and cerebrovascular endothelial cells) derived from the primary cultures and isolated from mice with ongoing EAE to express relevant co-stimulatory molecules and to process and present encephalitogenic myelin epitopes to a panel of myelin epitope-specific T cell clones and hybridomas will be assessed. These studies should enhance our understanding of the mechanisms of induction of epitope spreading and the effector role of these responses in the chronic pathogenesis of CNS autoimmune diseases. In addition, these studies will provide vital information relative to the use of specific immunoregulation for the treatment of pre-existing autoimmune disorders.
|Robinson, Andrew P; Caldis, Matthew W; Harp, Christopher T et al. (2013) High-mobility group box 1 protein (HMGB1) neutralization ameliorates experimental autoimmune encephalomyelitis. J Autoimmun 43:32-43|
|Getts, Daniel R; Turley, Danielle M; Smith, Cassandra E et al. (2011) Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells. J Immunol 187:2405-17|
|Adipue, Iris A; Wilcox, Joel T; King, Cody et al. (2011) Characterization of a novel and spontaneous mouse model of inflammatory arthritis. Arthritis Res Ther 13:R114|
|Chastain, Emily M L; Duncan, D'Anne S; Rodgers, Jane M et al. (2011) The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta 1812:265-74|
|Fu, Yan; Frederick, Terra J; Huff, Terry B et al. (2011) Paranodal myelin retraction in relapsing experimental autoimmune encephalomyelitis visualized by coherent anti-Stokes Raman scattering microscopy. J Biomed Opt 16:106006|
|Dogan, Rukiye-Nazan E; Long, Nancy; Forde, Eileen et al. (2011) CCL22 regulates experimental autoimmune encephalomyelitis by controlling inflammatory macrophage accumulation and effector function. J Leukoc Biol 89:93-104|
|Smarr, Charles B; Hsu, Chia-Lin; Byrne, Adam J et al. (2011) Antigen-fixed leukocytes tolerize Th2 responses in mouse models of allergy. J Immunol 187:5090-8|
|Miller, Stephen D; Karpus, William J; Davidson, Todd Scott (2010) Experimental autoimmune encephalomyelitis in the mouse. Curr Protoc Immunol Chapter 15:Unit 15.1|
|Turley, Danielle M; Miller, Stephen D (2010) Prospects for antigen-specific tolerance based therapies for the treatment of multiple sclerosis. Results Probl Cell Differ 51:217-35|
|Martin, Aaron J; McCarthy, Derrick; Waltenbaugh, Carl et al. (2010) Ethylenecarbodiimide-treated splenocytes carrying male CD4 epitopes confer histocompatibility Y chromosome antigen transplant protection by inhibiting CD154 upregulation. J Immunol 185:3326-36|
Showing the most recent 10 out of 70 publications