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Innate immune potential of primary lymphatic endothelial cells

Berendam, Stella J (2015) Innate immune potential of primary lymphatic endothelial cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Lymphatic endothelial cells (LECs) are loosely overlapping cells that line the lymphatic vasculature. In tissues, LECs are often located directly beneath the mucosal epithelial layer, and therefore, are likely to be among the first cells that come in contact with incoming pathogens and/or vaccine antigens and adjuvants when there is a breakage at the epithelial barrier. We are only starting to appreciate the role of LECs in the development of host innate and adaptive immune responses during infection or vaccine administration. This is largely due to the difficulties in studying LECs in vivo and the challenges in obtaining pure LEC cultures for study ex vivo. My work focused on isolation and establishment of primary LEC cultures derived from different tissue origins of commonly used animal models – ferrets and rhesus macaques – and assessment of the potential of these LECs to respond to pathogen-associated molecular patterns (PAMPs) or a subset of microbes (SIV/HIV-1). In addition, I also partially compared the phenotype and functionality of LECs to dendritic cells (DCs), an immune cell type that acts as a “bridge” between the host innate and adaptive immunity. My findings revealed that LECs were highly heterogeneous in their gene expression profiles. They also endogenously expressed multiple known viral entry and restriction factors for SIV/HIV-1. LECs responded to several PAMPs by producing proinflammatory cytokines/chemokines that are known to recruit immune cells to sites of inflammation. However, LECs were not highly susceptible or permissible to infection using genetically engineered, single-cycle competent SIV/HIV-1 or wild-type SIV. Interestingly, LECs expressed phenotypic markers that have been shown to be expressed by DCs and showed some functional similarities. LECs were able to take up and process model antigens, although it was not determined if these antigens were presented by MHC I and II molecules. These findings are of public health importance because they expand our knowledge of the emerging potential of LECs as key players in innate immunity during pathogen-host interactions or vaccinations. Improving our understanding of LECs will positively impact our knowledge of mucosal infections and will help in development of improved treatment and vaccination strategies. These primary cells will serve as tools to study LEC immunobiology and will also be useful in development of vaccines/therapeutics for human diseases of public health importance that target LEC and/or its crosstalk with other immune cells.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Berendam, Stella Jsjb84@pitt.eduSJB84
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorReinhart, Todd A.reinhar@pitt.eduREINHAR
Committee MemberMarques, Ernesto T. A.marques@pitt.eduMARQUES
Committee MemberJenkins, Frank J.fjenkins@pitt.eduFJENKINS
Committee MemberFerrell, Robert Erferrell@helix.hgen.pitt.eduRFERRELL
Date: 29 June 2015
Date Type: Publication
Defense Date: 13 April 2015
Approval Date: 29 June 2015
Submission Date: 7 April 2015
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 200
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: lymphatic
Date Deposited: 29 Jun 2015 14:57
Last Modified: 19 Dec 2016 14:42
URI: http://d-scholarship.pitt.edu/id/eprint/24630

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