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Regulation of renal immunity and immunopathology by interleukin-17

Ramani, Kritika (2017) Regulation of renal immunity and immunopathology by interleukin-17. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Pro-inflammatory cytokine IL-17 has been implicated in tissue damage associated with various autoimmune diseases. IL-17 is also known to contribute in immunity against bacterial and fungal pathogens. Most research over the past decade focused on understanding how IL-17- producing cells are generated, but far less is known about the organ specific responses of IL-17. In this thesis, we delineate the specific roles for IL-17 in the kidney, an organ susceptible to both auto-inflammatory conditions and infection. With the help of murine models, we outline the IL-17-driven responses in infection and autoimmunity. We studied the role for IL-17 mediated protection in disseminated candidiasis, a fatal nosocomial infection associated with high mortality. We discovered a previously unappreciated connection between IL-17 and the kallikrein- kinin system in renal protection against disseminated candidiasis. Simultaneously, we defined the cellular and molecular events in IL-17 driven renal tissue damage in murine models of autoimmune glomerulonephritis and lupus nephritis. Our results suggest that the kidney specific role of IL-17 is in the regulation of innate immune cells associated with kidney pathology. In addition, we were the first to show that neutralization of IL-17 ameliorated renal pathology in the autoimmune glomerulonephritis model. The consequence of unchecked renal inflammation is irreversible damage in the kidney, leading to fibrosis. In the case of inflammation mediated end organ fibrosis, the role for pro-fibrotic or anti-fibrotic role for IL-17 is debatable. We focused our attention on the role for IL-17-mediates immune responses in the kidney in a mouse model of fibrosis. We uncovered a surprisingly protective, anti-fibrotic role for IL-17 in the kidney that was driven by the IL-17-Klk1 axis. In summary, our findings have advanced the understanding of IL-17 mediated immunity and immunopathology and opens up the potential to develop therapeutic strategies based on the context of the disease.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ramani, Kritikakrr57@pitt.edukrr57
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorBiswas, Parthapsb13@pitt.edu
Date: 18 January 2017
Date Type: Publication
Defense Date: 9 November 2016
Approval Date: 18 January 2017
Submission Date: 8 December 2016
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 190
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Interleukin-17, disseminated candidiasis, autoimmune glomerulonephritis, renal fibrosis, C.albicans, kidney
Date Deposited: 18 Jan 2017 15:46
Last Modified: 18 Jan 2017 15:46
URI: http://d-scholarship.pitt.edu/id/eprint/30517

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