Herpes Stromal Keratitis (HSK) is one of the leading causes of infectious blindness in the developed world. HSK is characterized by corneal damage and scarring that results from a Th1 cytokine-mediated immunopathology. It is triggered by reactivation of HSV-1 from latency in sensory neurons of the trigeminal ganglion (TG) and its subsequent transport to the eye through axons that innervate the cornea. My thesis work explored key components of both the HSV-specific CD8+ T cell response that maintains HSV-1 latency in sensory neurons, and the opposing roles of the immune system in controlling HSV-1 replication in the cornea and promoting the immunopathology that results in corneal scarring and blindness. We hypothesized and provide strong supporting evidence that CD4+ T cells act as a double-edged sword, on the one hand providing critical help to HSV-specific CD8+ T cells that enables them to control viral latency through avoidance of exhaustion within the infected TG. On the other hand, we employed HSV-specific CD4+ T cell clones to explore their role in orchestrating the immunopathology associated with HSK. We also explored the Ying and Yang of dendritic cell involvement in HSK. While our previous studies suggested a role for DC in promoting HSK, we now employ a unique localized DC depletion model to establish that first responding DCs are critical in mobilizing both the innate and adaptive immune response that clears virus from the cornea. Finally, we employed newly available recombinant mouse strains lacking IL-12p40, p35, or both p40 and p35 to explore the involvement of the IL-12 cytokine family in HSK. The heterodimeric cytokines IL-12 (p40/p35) and IL-23 (40/p19) are thought to regulate HSK by promoting production of the requisite TH1 cytokine IFN-. However, we find that HSK development does not require IL-12p40 and is thus independent of IL-12 and IL-23. Instead, HSK late progression actually requires a previously unrecognized IL-12p40-independent, proinflammatory function of IL-12p35.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-05042010-111900 |
| Date | 07 May 2010 |
| Creators | Frank, Gregory M |
| Contributors | Robert L Hendricks, Pawel Kalinski, Angus W Thomson, Olivera J Finn, Paul R Kinchington |
| 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-05042010-111900/ |
| 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 0.0019 seconds