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Regulation of Immunopathology in Mycobacterium tuberculosis infection

Windish, Hillarie Plessner (2008) Regulation of Immunopathology in Mycobacterium tuberculosis infection. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Approximately one third of the world's 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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Windish, Hillarie Plessnerhip@pitt.eduHIP
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFlynn, JoAnne L.joanne@pitt.eduJOANNE
Committee MemberNorris, Karen A.kan1@pitt.eduKAN1
Committee MemberMorel, Penelope A.morel@pitt.eduMOREL
Committee MemberSalter, Russell D.rds@pitt.eduRDS
Committee MemberRoss, Ted M.tmr15@pitt.eduTMR15
Date: 17 June 2008
Date Type: Completion
Defense Date: 8 May 2008
Approval Date: 17 June 2008
Submission Date: 29 May 2008
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: adhesion molecule; BLT-1; cytokine; ICAM-1; LTB4; osteopontin; TNF; tuberculosis
Other ID:, etd-05292008-141858
Date Deposited: 10 Nov 2011 19:46
Last Modified: 15 Nov 2016 13:44


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