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dc.contributor.advisorZaghouani, Habibeng
dc.contributor.authorJain, Renu, 1979-eng
dc.date.issued2008eng
dc.date.submitted2008 Springeng
dc.descriptionThe entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.eng
dc.descriptionTitle from PDF of title page (University of Missouri--Columbia, viewed on April 1, 2010).eng
dc.descriptionVita.eng
dc.descriptionThesis advisor: Habib Zaghouani.eng
dc.description"May 2008"eng
dc.descriptionPh. D. University of Missouri-Columbia 2008.eng
dc.description.abstract[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Type I diabetes (TID) or insulin-dependent diabetes mellitus (IDDM) is an immunemediated disease in which the beta ([beta]) cells of the pancreatic islets of Langerhans are destroyed as a consequence of inflammatory reactions triggered by activation of T cells specific for [beta]-cell associated antigens. Numerous approaches have been tested in the non obese diabetic (NOD) mouse, a commonly studied animal model of TID, to treat disease but very few have made it to clinical settings because of two main reasons. Firstly, most of these therapies are non-antigen specific and target all the T cells, thereby inducing a state of generalized immunosuppression. Secondly, the majority of interventions are preventive. As many TID patients are identified only at diabetes onset, agents that can reverse disease at late stages are urgently required. Two approaches have been developed to meet the above mentioned requisites for treatment of TID. In the first study, glutamic acid decarboxylase (GAD) sequence 206-220 (designated GAD2), representing a late stage diabetic epitope, was genetically incorporated into an Ig molecule to magnify tolerance and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the pre-insulitis phase but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration as well as [beta]-cell division and restored normoglycemia when given to hyperglycemic mice at the pre-diabetic stage. This was dependent on the induction of splenic IFN? that inhibited IL-17 production. In fact, neutralization of IFN[lowercase gamma] led to a significant increase in the frequency of Th17 cells and the treatment became non-protective. Thus, treatment with Ig-GAD2 induces IFN[lowercase gamma] that reverses TID and restores normoglycemia in an antigen-specific manner most likely by localized bystander suppression of pathogenic IL-17-producing cells. In the second study, a tolerogenic population of NOD dendritic cells (DC) was identified that upon being loaded with diabetic antigens could mediate protection from disease in an antigenspecific manner. In fact, treatment with the CD8[alpha][superscript -]CD4[superscript -] CD11c[superscript +] DC subset reduced destructive infiltration within the islets, induced antigen-specific IFN[lowercase gamma] and IL-10 producing T regulatory type 1 (Tr1) T cells and expanded CD4[superscript -] CD25[superscript +] Foxp3[superscript hi] regulatory T (Treg) cells in the spleen. The protective function was due to the ability of DCs to traffic efficiently to the non-inflammatory organ spleen but not to the inflammatory organs pancreatic lymph nodes and pancreas. Thus, the CD8[alpha]CD4[superscript -] CD11c[superscript +] DC subset induces regulatory T cells in spleen that likely interfere with the influx of diabetogenic effector T cells to the pancreas and/or the pathogenic function of effector cells, thereby reducing destructive islet infiltration and mediating protection from disease.eng
dc.description.bibrefIncludes bibliographical referenceseng
dc.format.extentxi, 112 pageseng
dc.identifier.oclc603560624eng
dc.identifier.urihttps://hdl.handle.net/10355/6869
dc.identifier.urihttps://doi.org/10.32469/10355/6869eng
dc.languageEnglisheng
dc.publisherUniversity of Missouri--Columbiaeng
dc.relation.ispartofcommunityUniversity of Missouri--Columbia. Graduate School. Theses and Dissertationseng
dc.rightsAccess is limited to the campus of the University of Missouri--Columbia.eng
dc.subject.lcshDiabetes -- Treatmenteng
dc.subject.lcshDiabetes -- Immunotherapyeng
dc.subject.lcshGGenetic regulationeng
dc.subject.lcshDendritic cellseng
dc.subject.lcshT cellseng
dc.subject.lcshInterleukinseng
dc.subject.lcshDiabetes -- Diet therapyeng
dc.subject.lcshMacrophages -- Activationeng
dc.subject.meshDiabetes Mellitus, Type 1 -- immunologyeng
dc.subject.meshDiabetes Mellitus, Type 1 -- therapyeng
dc.subject.meshInterferon-gamma -- metabolismeng
dc.subject.meshInterleukin-17 -- anatogonists & inhibitorseng
dc.subject.meshImmunotherapyeng
dc.subject.meshGene Expression Regulationeng
dc.subject.meshDendritic Cells -- immunologyeng
dc.subject.meshT-Lympocyte Subsets -- immunologyeng
dc.subject.meshMice, Inbred NODeng
dc.titleImmunotherapy for autoimmune diabeteseng
dc.typeThesiseng
thesis.degree.disciplineMicrobiology (Medicine) (MU)eng
thesis.degree.grantorUniversity of Missouri--Columbiaeng
thesis.degree.levelDoctoraleng
thesis.degree.namePh. D.eng


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