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Immunomodulation of experimental autoimmune encephalomyelitis: targeting the autoreactive T cell and the cytokine macrophage migration inhibitory factor

Powell, Nicole Damico
http://rave.ohiolink.edu/etdc/view?acc_num=osu1141052089

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Medical Microbiology and Immunology.
Immunomodulatory therapies have been successful in MS and EAE. To determine a possible immunomodulatory target at the level of the T cell receptor/antigen/MHC interaction, the activation parameters of autoreactive T cells were assessed by differential stimulation of spleen cells from Va4/Vb8.2 TCR transgenic mice with MBP or the immunodominant epitope of MBP, NAc1-11. To determine the encephalitogenic potential of these cells, either MBP or NAc1-11 stimulated cells were adoptively transferred to syngeneic B10.PL recipients. Only recipients of NAc1-11 stimulated cells showed clinical signs of EAE. NAc1-11 stimulated cells secreted increased levels of IL-12, IFN-g and IL-2. MBP stimulated cells secreted increased IL-4 and IL-10. The MBP stimulated cells, as well as cells stimulated with an extended N-terminal peptide, NAc1-20, were able to suppress Th1 proliferation in vitro and protect from active EAE induction. In addition, a subset of CD4+ T cells, which are Vb8.2-, are being activated by MBP and NAc1-20, and this subset is protective against EAE induction. These findings support that MBP, and its N-terminal peptide NAc1-20 are capable of producing CD4+ T cells that can protect from EAE through activation of a regulatory CD4+ population and modulation of cytokine production. To determine potential immunomodulation at the level of cytokine production, the inflammatory cytokine macrophage migration inhibitory factor (MIF) was investigated. MIF has been implicated in the pathogenesis of inflammatory and autoimmune diseases. The role of MIF in the progression of EAE was explored using MIF-/- mice. Wild-type, C57BL6X129, mice showed a progressive disease course, while MIF-/- mice of the same strain exhibited acute signs but no further progression of clinical disease. MIF-/- mice displayed markedly elevated corticosterone (CORT) levels, significant decreases in the inflammatory cytokines TNF-a, IFN-g, IL-2, and IL-6, and significant increases in the anti-inflammatory cytokines IL-4 and IL-10 before, during and after EAE onset. These findings support that MIF is an important mediator of EAE progression through glucocorticoid antagonism and upregulation of the inflammatory response. Taken together, through the activation of a subset of MBP specific CD4+ Th2/regulatory cells or through targeting the cytokine MIF, new therapeutic targets for MS have been identified.
Caroline Whitacre (Advisor)
Health Sciences, Immunology
MS; EAE; MIF; Glucocorticoids

Recommended Citations

Citations

  • Powell, N. D. (2006). Immunomodulation of experimental autoimmune encephalomyelitis: targeting the autoreactive T cell and the cytokine macrophage migration inhibitory factor [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1141052089

    APA Style (7th edition)

  • Powell, Nicole. Immunomodulation of experimental autoimmune encephalomyelitis: targeting the autoreactive T cell and the cytokine macrophage migration inhibitory factor. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1141052089.

    MLA Style (8th edition)

  • Powell, Nicole. "Immunomodulation of experimental autoimmune encephalomyelitis: targeting the autoreactive T cell and the cytokine macrophage migration inhibitory factor." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1141052089

    Chicago Manual of Style (17th edition)

osu1141052089
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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.
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