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The response of the lymphatic endothelium to inflammation and infection in in vitro and in vivo systems

Pegu, Amarendra (2007) The response of the lymphatic endothelium to inflammation and infection in in vitro and in vivo systems. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Pegu, Amarendraamarpegu@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairReinhart, Todd Areinhar@pitt.eduREINHAR
Committee MemberFinegold, Daviddavid.finegold@hgen.pitt.eduDNF
Committee MemberFlynn, JoAnne Ljoanne@mgb.pitt.eduJOANNE
Committee MemberBarratt-Boyes, Simonsmbb@pitt.eduSMBB
Date: 27 September 2007
Date Type: Completion
Defense Date: 17 July 2007
Approval Date: 27 September 2007
Submission Date: 25 July 2007
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: CCL21; LYVE-1; Podoplanin
Other ID: http://etd.library.pitt.edu/ETD/available/etd-07252007-124229/, etd-07252007-124229
Date Deposited: 10 Nov 2011 19:53
Last Modified: 15 Nov 2016 13:46
URI: http://d-scholarship.pitt.edu/id/eprint/8591

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