Mycobacterium tuberculosis continues to be a leading cause of death by an infectious agent world wide with approximately two million deaths attributable to it annually. Once infected, the host mounts a robust Th1 type immune response that contains, but does not eliminate the bacteria. A small percentage (5-10%) fail to contain the infection, develop active disease, and are contagious. Most remain asymptomatic and are considered latently infected. BCG, while the gold standard for vaccination, ultimately appears to limit disease, but not prevent infection. In addition, chemotherapeutic treatment is long, requires multiple agents, and compliance is difficult to maintain. With one third the worlds population infected, inadequate vaccine efficacy, and difficult treatment regimen, it is imperative that a better understanding of which factors are responsible for containment of the infection be achieved. CD4 T cells are an essential component of the immune response that controls M. tuberculosis. CD4 T cells are able to both promote inflammation and dampen its effect. As a pro-inflammatory Th1 cell, these cells secrete pro-inflammatory cytokines, participate in macrophage and dendritic cell activation and help prime CD8 T cells. As regulatory T cells, CD4 T cells prevent autoimmunity and may act to protect surrounding tissue from immunopathologic damage. One main function of pro-inflammatory CD4 T cells is IFNγ production, however other cells can and do produce IFNγ. In addition, the role of regulatory T cells during infection and how they relate to disease progression has yet to be elucidated. The work presented in this dissertation provides a new model for addressing the role of IFNγ from sources other than CD4 T cells, and addresses what pro-inflammatory functions they may have in addition to IFNγ production. In addition, these studies address regulatory T cells and the anti-inflammatory effects of long term IL-12 treatment as well as Tregs relationship to disease outcome in non-human primates.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12222010-135410 |
| Date | 23 December 2010 |
| Creators | Green, Angela Marie |
| Contributors | Karen A Norris Ph.D., Robert L Hendricks Ph.D., Anuradha Ray Ph.D., JoAnne L. Flynn Ph.D., Gerard J. Nau M.D., Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-12222010-135410/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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