Approximately one third of the worlds population is infected with Mycobacterium tuberculosis, which was responsible for about 1.6 million deaths in 2005. In spite of continuing advances in understanding host response to this infection, generation and maintenance of the host immune response remains unclear. In this thesis, we investigate molecules involved in the generation and maintenance of the host response, specifically the granuloma, to M. tuberculosis. We investigated the role of TNF antagonists in reactivation of tuberculosis, and showed that while anti-TNF antibody is superior to TNFR2-Fc fusion molecule in penetrating the granuloma, any blockade of TNF compromises control of acute tuberculosis. We hypothesized that TNF is required for priming T cell responses and that TNF-inducible chemokine receptors function redundantly, allowing one chemokine to compensate in the absence of another. Here, we show that TNF is not required to prime the adaptive immune response, and that TNF-inducible chemokines CXCR3 and CCR5 are simultaneously expendable, refuting the compensation hypothesis in these two chemokines. Reports have implicated unexplored inflammatory molecules in host response to M. tuberculosis infection. We hypothesized that the small chemotactic molecule LTB4 and its receptor BLT1 increase pathology during M. tuberculosis infection. We also hypothesized that osteopontin is required for mediating an effective immune response to tuberculosis by mediating Th1 priming and lymphocyte migration. We show here that neither BLT1 nor osteopontin play a significant role in the inflammatory response to M. tuberculosis. Finally, we investigated the role of ICAM-1 in priming effector and regulatory T cells in response to tuberculosis. We report that ICAM-1 is dispensable for priming and migration of effector T cells, but that ICAM-1 is required for production of inducible Foxp3+ T regulatory cells via TGFâ1 stimulation. We hypothesize that the reduction in T regulatory cells exacerbates the immune response, allowing greater inflammation in the lungs, potentially causing overwhelming inflammation. This body of work contributes to the understanding of the host response to tuberculosis by investigating activity of cytokines, chemotactic molecules and adhesion molecules in balancing the host response to M. tuberculosis infection.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-05292008-141858 |
| Date | 17 June 2008 |
| Creators | Windish, Hillarie Plessner |
| Contributors | Ted M. Ross, Penelope A. Morel, Russell D. Salter, Karen A. Norris, JoAnne L. Flynn |
| 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-05292008-141858/ |
| Rights | restricted, 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. |
Page generated in 0.003 seconds