The lymphatic endothelium is involved in the drainage of interstitial fluid and in the migration of immune cells like dendritic cells (DCs) from the periphery to draining lymph nodes (LNs). Tuberculosis has been declared a pandemic infectious disease accounting for more than 2 million deaths annually and is caused by the intracellular bacteria, Mycobacterium tuberculosis. The chronic inflammatory response to M. tuberculosis infection is characterized by the formation of granulomatous structures in the pulmonary compartments of infected individuals. These structures contain excess interstitial fluid and are enriched with immune cells including DCs. Therefore, the lymphatic vessels might play important roles in regulating drainage of fluid and migration of immune cells from granulomas to the draining LNs. My hypothesis was that there is an increased concentration of lymphatic vessels in these granulomatous structures and that the inflammatory environment including mycobacterial components present in granulomas and at other sites of infection elicit an inflammatory response from these lymphatic vessels which contribute to the overall immune response to M. tuberculosis infection. To address this hypothesis I have examined the distribution of lymphatic vessels in granulomatous and LN tissues obtained from nonhuman primates infected with M. tuberculosis and analyzed their expression of multiple chemokines and lymphatic markers. In addition, I evaluated the response of LECs to inflammatory mediators that included multiple TLR ligands, M. tuberculosis components and cytokines. I observed an association of lymphatic vessels with granulomas, and found that there was heterogeneity in the expression of chemokines and lymphatic markers by LECs in tissues. I also found that primary human LECs expressed multiple TLR molecules and responded to TLR ligands, cytokines and M. tuberculosis components by increasing expression of inflammatory chemokines, cytokines and adhesion molecules. These LECs also demonstrated phenotypic similarities with DCs. Overall my findings support the involvement of the lymphatic endothelium in the inflammatory immune response to pathogens like M. tuberculosis. From the perspective of public health relevance, these studies provide direction in the development of new therapeutic targets against M. tuberculosis infections and aid in the development of better adjuvants for vaccines for infectious diseases and cancers.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-07252007-124229 |
| Date | 27 September 2007 |
| Creators | Pegu, Amarendra |
| Contributors | Simon Barratt-Boyes, David Finegold, JoAnne L. Flynn, Todd A Reinhart |
| 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-07252007-124229/ |
| 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. |
Page generated in 0.0017 seconds