(From the Applicant?s Abstract): The studies proposed herein will: (i) determine the roles of membrane FasL (mFasL) and soluble FasL(sFasL) in neutrophil-mediated inflammation within the eye and most importantly, (ii) determine whether sFasL can be used to downregulate neutrophil-mediated inflammation and prevent neutrophil-mediated ocular damage. Preliminary studies demonstrate that within the immune privileged eye, mFasL activates neutrophils and initiates innate immunity, while sFasL inhibits neutrophil activation ad prevents innate immunity. Most compelling though, was the ability of sFasL to block the pro-inflammatory effects of mFasL when both sFasL when both sFasL and mFasL were equally expressed within the eye. The proposed studies will utilize a novel method of expressing DNA directly within the cornea to characterize, in vivo, the inflammatory response induced by the different forms of FasL expressed within the corneal stroma. The ability of both mFasL and sFasL to directly activate neutrophils will be assessed in vitro using stromal cells transfected with the different FasL cDNAs. The final set of experiments will determine, in vivo, whether sFasL blocks neutrophil mediated inflammation in the cornea, and to elucidate, in vitro, the mechanism by which sFasL blocks mFasL induced neutrophil activation. We anticipate that these studies will yield new information as to how FasL regulates inflammation within the eye, and possibly lead to the development of new treatments using the soluble form of FasL to prevent ocular damage secondary to neutrophil mediated inflammation.
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| Gregory, Meredith S; Koh, Sean; Huang, Eric et al. (2005) A novel treatment for ocular tumors using membrane FasL vesicles to activate innate immunity and terminate immune privilege. Invest Ophthalmol Vis Sci 46:2495-502 |
| Gregory, Meredith S; Repp, Amanda C; Holhbaum, Andreas M et al. (2002) Membrane Fas ligand activates innate immunity and terminates ocular immune privilege. J Immunol 169:2727-35 |
