CD8+ T Cells Are Required for the Therapeutic Action of Glatiramer Acetate in Autoimmune Demyelinating Disease

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dc.contributor.advisorNiederkorn, Jerry Y.en
dc.contributor.committeeMemberEagar, Todd N.en
dc.contributor.committeeMemberPasare, Chandrashekharen
dc.contributor.committeeMemberStreet, Nancy E.en
dc.contributor.committeeMemberKarandikar, Nitin J.en
dc.creatorTyler, Andrew Farleyen
dc.date.accessioned2015-06-01T21:58:20Z
dc.date.available2015-06-01T21:58:20Z
dc.date.created2015-05
dc.date.issued2013-06-28
dc.date.submittedMay 2015
dc.date.updated2015-06-01T21:57:51Z
dc.description.abstractGlatiramer acetate (GA, Copaxone®) is an FDA-approved immunomodulatory therapy for multiple sclerosis (MS), an immune-mediated demyelinating disease of the central nervous system. Our group has previously shown that GA therapy induces CD8+ T cell responses responsible for suppression of CD4+ T cell responses in MS patients. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we also demonstrated that CD8+ T cells are necessary in mediating the therapeutic effects of GA, and adoptive transfer of GA-induced CD8+ T cells resulted in amelioration of EAE, establishing a role as a viable immunotherapy in demyelinating disease. Here, we show that GA treatment, as well as the suppressive function of GA CD8+ T cells, requires IFNγ and perforin, but not IL-10, expression and activation by non-classical MHC class I molecules both in vitro and in vivo. GA-induced regulatory myeloid cells, previously shown to activate CD4+ regulatory T cells in an antigen-independent manner, depend on CD8+ T cells and MHC class I expression to suppress disease in vivo, an effect mediated by MHC class I-mediated induction of CD8+, but not CD4+, T cell responses. GA induces an anti-inflammatory “type 2” phenotype in monocytes in vivo that is unnecessary for the suppression of disease. The drug also inhibits the expression of surface markers of maturation such as CD11c and MHC class II. GA CD8+ T cells reduce the proliferative potential of autoimmune, neuroantigen-specific CD4+ T cells and induce CD4+CD25+Foxp3+ regulatory T cells in vivo. Additionally, several MHC class I-binding peptide epitopes associated with GA treatment of dendritic cells were identified by LC/MS-MS and tested for disease suppression and ability to activate GA CD8+ T cells. These studies demonstrate an essential role for CD8+ T cells in GA therapy and identify their potential as an adoptive immunotherapeutic agent.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc910559213
dc.identifier.urihttps://hdl.handle.net/2152.5/1594
dc.language.isoenen
dc.subjectCD8-Positive T-Lymphocytesen
dc.subjectImmunologic Factorsen
dc.subjectMultiple Sclerosis, Relapsing-Remittingen
dc.titleCD8+ T Cells Are Required for the Therapeutic Action of Glatiramer Acetate in Autoimmune Demyelinating Diseaseen
dc.typeThesisen
dc.type.materialTexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineImmunologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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