Theses and Dissertations at Montana State University (MSU)
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Item Molecular characterization of the primary adhesion mechanisms that direct [gamma/delta] T cells to epithelial-associated tissues(Montana State University - Bozeman, College of Agriculture, 1994) Walcheck, Bruce KennethItem Analysis and characterization of tissue specific accumulation of TCR-defined [gamma delta] T cell subsets in the bovine system(Montana State University - Bozeman, College of Agriculture, 2000) Wilson, EricItem Inhibition of alloantigen-specific T-cell mediated cytotoxicity by antisera specific for the mouse Ly-5 antigen(Montana State University - Bozeman, College of Agriculture, 1984) Davis, Brian ScottItem Biochemical and functional analysis of a novel lineage-specific gamma delta T cell surface antigen (GD3.5Ag)(Montana State University - Bozeman, College of Agriculture, 1997) Jones, Ward McAlisterItem Primary and secondary in vitro generation of bovine cytotoxic T lymphocytes(Montana State University - Bozeman, College of Agriculture, 1984) Senta, Kathleen ElizabethItem The effect of calcium-tuned cyclotron resonance upon the proliferation rate of adult T-cell leukemia cells(Montana State University - Bozeman, College of Engineering, 1989) Simon, Scott PatrickItem Characterization of the gamma delta T cell response to Amphotericin B(Montana State University - Bozeman, College of Agriculture, 2012) Mitchell, Angela Marie; Chairperson, Graduate Committee: Mark JutilaGamma delta T cells mediate a wide variety of functions within the host. Putative roles for these cells include tumor infiltration and clearance, pathogen detection and response, tissue repair and homeostasis, and augmentation or regulation of the inflammatory response. However, the precise roles gamma delta T cells play in the immune response to diseases and other stress-inducing states within the host are still unclear. Therefore, it is of interest to determine what types of molecules and signals are involved in the activation of these cells, altering their functional responses in disease states. As such, we screened numerous natural and synthetic compounds for their ability to activate bovine gamma delta T cells. Interestingly, a clinically approved antifungal drug, Amphotericin B, was found to prime the gamma delta T cells for activation. We demonstrate that Amphotericin B can utilize different receptors in a tissue-specific manner, making it a rather unique agonist for use as a therapeutic adjuvant. Amphotericin B was also able to act synergistically with other human and bovine gamma delta T cell agonists for enhanced activation of these cells. Furthermore, alternate formulations of the drug displayed different capabilities to stimulate gamma delta T cells. Interestingly, Amphotericin B was found to enhance the clearance of bacterial infections in mice, and the drug demonstrated potential as a potent vaccine adjuvant. Overall, Amphotericin B affects gamma delta T cell responses, and these cells are involved in a wide variety of immune responses. Therefore, Amphotericin B has the potential to be administered so as to manipulate the gamma delta T cell response for the benefit of the host during infectious disease.Item Vaccine platform for infection or autoimmune diseases using an ETEC fimbrial scaffold(Montana State University - Bozeman, College of Agriculture, 2009) Jun, SangMu; Chairperson, Graduate Committee: David Pascual.The expression of enterotoxigenic Escherichia coli (ETEC) fimbriae (colonization factor antigen I (CFA/I) or K99) on the surface of a Salmonella vaccine vector confers protection against ETEC challenge. Application of such fimbriae as a treatment for the proinflammatory disease, experimental autoimmune encephalomyelitis (EAE), or as a molecular scaffold for heterologous antigen expression by cloning enterohemorrhagic E. coli (EHEC) LPS peptide mimetics into the K99 fimbriae to produce a dual vaccine for ETEC/EHEC was investigated. The expression of CFA/I fimbriae by a Salmonella vaccine vector stimulates a biphasic T helper (Th) cell response and suppresses proinflammatory responses suggesting that CFA/I fimbriae may be protective against proinflammatory diseases. To test this hypothesis, SJL/J mice were vaccinated with Salmonella-CFA/I vaccine 1 or 4 wks prior to induction of EAE induced with encephalitogenic proteolipid protein (PLP) peptide, PLP₁₃₉-₁₅₁. Mice receiving Salmonella-CFA/I vaccine recovered completely from the mild acute clinical disease and showed only mild inflammatory infiltrates in the spinal cord. This protective effect was accompanied by a loss of encephalitogenic IFN-gamma secreting Th1 cells and replaced with increases in IL-4-, IL-10-, and IL-13- producing Th2 cells. These data suggest that Salmonella-CFA/I is an anti-inflammatory vaccine capable of suppressing proinflammatory cells to protect against EAE via immune deviation. To obtain an effective nasal vaccine for ETEC, the fanC gene of ETEC K99 major structural gene was cloned onto the reovirus adhesin, protein sigma1, which has been shown as an M cell targeting molecule. Although FanC/protein sigma1 fusion protein was successfully expressed, this vaccine failed to elicit immune responses against native FanC protein, presumably because of improper protein folding. Using K99 fimbriae as a molecular scaffold, a LPS peptide mimetic for EHEC was cloned into the fanH gene of K99 fimbriae minor structural gene to enable multiple antigenic peptide expression, resulting in an ETEC/EHEC dual vaccine. Insertion of peptide mimetic into fanH gene had no adverse effect on the formation of polymerized K99 fimbriae. However, various oral immunization regimens failed to induce the protective secretory IgA responses against the LPS mimetic peptide, although serum IgG antibodies were induced.Item Select Procyanidins induce gammadelta T cell activation and proliferation(Montana State University - Bozeman, College of Agriculture, 2008) Holderness, Jeffrey Scott; Chairperson, Graduate Committee: Mark Jutila.Many pharmaceutical drugs in use today were originally identified in plants from traditional medicine. However, there remain many plants in traditional medicine that produce confusing immune responses and are therefore unlikely candidates for pharmaceutical drugs. The effects of some of the traditional medicines that induce these confusing immune responses may now be explained by recent advances in the characterization of our immune system, namely in our understanding of the unique functions of the gammadelta T cell. These gammadelta T cell functions include tissue repair and homeostasis, cancer infiltration and clearance, pathogen detection and cytokine response, and antigen presentation. Although there are currently therapies being studied to increase the effector function of gammadelta T cells, these techniques are only active on a limited population of gammadelta T cells, the human Vdelta2 subset. Although these cells are potent effectors against pathogens and some cancers, Vdelta2 T cells demonstrate a restricted tissue distribution and limited effector function in other gammadelta T cell host defense responses. As such, we screened compound libraries and traditional medicines for agonists with activity encompassing alternative gammadelta T cell subsets. Tannins derived from select plant species are able to fulfill this role as demonstrated by the activation and expansion of gammadelta T cell subsets not responsive to current gammadelta T cell expansion therapies. The ability of tannins to expand these gammadelta T cell populations will potentially increase the therapeutic range of gammadelta T cells and may be used as treatments for wound healing as well as in the clearance of solid tumor cancers.Item Identification of immunodominant T cell epitopes from enterotoxigenic E. coli colonization factor antigen I (CFA/I) responsible for T helper cell cytokines(Montana State University - Bozeman, College of Agriculture, 2012) Holderness, Kathryn; Chairperson, Graduate Committee: David PascualEnterotoxigenic Escherichia coli (ETEC) are a major cause of diarrheal disease contracted by consuming contaminated food or water. ETEC is able to adhere to the small intestine by utilizing pili or fimbriae, one of which is the fimbriae Colonization Factor Antigen/I (CFA/I). The extracellular portion of CFA/I fimbriae is comprised of two fimbrial subunits, cfaB and cfaE. Expression of CFA/I fimbriae on the surface of an attenuated Salmonella vaccine vector, Salmonella-CFA/I, results in a biphasic T cell response in immunized mice. This response is characterized by the initial production of Th2-type cytokines, including IL-4 and IL-5, followed by a shift after 4 weeks toward an IFN-gamma-associated, Th1 response. Restimulation of CD4 + T cells from Salmonella-CFA/Iimmunized mice with CFA/I fimbriae also generates the anti-inflammatory cytokine, IL-10. Salmonella-CFA/I is able to generate antigen-independent Foxp3 + regulatory T cells, which are able to reduce symptoms of Experimental Autoimmune Encephalomyelitis in immunized SJL mice and Collagen Induced Arthritis in DBA/I and C57BL/6 mice, via production of IL-10 and TGF-beta by phenotypically distinct regulatory T cell subsets. The following research describes the contribution of cfaB and cfaE to the observed therapeutic and immunological responses. This was measured by independently expressing recombinant cfaB and cfaE proteins and evaluating the associated cytokine responses from the co-culture of these proteins with CD4 + T cells from immunized mice. Major Histocompatibility Complex II-restricted immunodominant regions were also mapped for both cfab and cfae proteins using cytokine ELISAs, ELISPOTs, Proliferation Assays, and flow cytometry. We mapped an IFN-gamma-producing peptide from cfaB and an IL-4-producing peptide from cfaE. We further determined that co-culture with peptides from both fimbrial proteins is able to generate regulatory T cell-associated cytokines including IL-10 and TGF-beta as well as the newly described suppressive cytokine, IL-35. These results show that the immune responses to cfaB and cfaE are mediated by multiple immunodominant regions within each protein.