Infiltration of neutrophils and eosinophils from the limbal vessels to the corneal stroma involves adherence to vascular endothelial cells, and transmigration across this cell layer into the corneal stroma. The composition of the inflammatory cell infiltrate depends on the selective expression of vascular cell adhesion molecules, and on production of specific chemotactic stimuli.
The Specific Aims outlined in this proposal are focused on determining the molecular basis for immune-complex mediated recruitment of neutrophils and eosinophils to the cornea in a murine model for Onchocerca volvulus keratitis (river blindness). The proposed studies will assess the role of C5a, and. will determine if Fc gamma receptor expression is required for production of chemotactic and immunoregulatory cytokines by neutrophils and eosinophils in the cornea, including KC, MIP-2, MIP-1 alpha, eotaxin, RANTES, TNF-alpha, IFN-gamma, and IL-4. Studies will also determine the relative importance of vascular cell adhesion molecules PECAM-1, VCAM-1, ICAM-1 and P-selectin in recruitment of these cells. The long-term goal of these studies is to identify potential targets for immune based therapy that can be applied to O.volvulus keratitis and to other ocular conditions in which neutrophils or eosinophils are predominant, such as herpes simplex keratitis and ocular allergy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY010320-08
Application #
6196180
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
1993-12-01
Project End
2003-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
8
Fiscal Year
2001
Total Cost
$331,224
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Carlson, Eric C; Sun, Yan; Auletta, Jeffery et al. (2010) Regulation of corneal inflammation by neutrophil-dependent cleavage of keratan sulfate proteoglycans as a model for breakdown of the chemokine gradient. J Leukoc Biol 88:517-22
Gentil, Katrin; Pearlman, Eric (2009) Gamma interferon and interleukin-1 receptor 1 regulate neutrophil recruitment to the corneal stroma in a murine model of Onchocerca volvulus keratitis. Infect Immun 77:1606-12
Turner, Joseph D; Langley, R Stuart; Johnston, Kelly L et al. (2009) Wolbachia lipoprotein stimulates innate and adaptive immunity through Toll-like receptors 2 and 6 to induce disease manifestations of filariasis. J Biol Chem 284:22364-78
Du, Yiqin; Carlson, Eric C; Funderburgh, Martha L et al. (2009) Stem cell therapy restores transparency to defective murine corneas. Stem Cells 27:1635-42
Lin, Michelle; Jackson, Patricia; Tester, Angus M et al. (2008) Matrix metalloproteinase-8 facilitates neutrophil migration through the corneal stromal matrix by collagen degradation and production of the chemotactic peptide Pro-Gly-Pro. Am J Pathol 173:144-53
Gillette-Ferguson, Illona; Daehnel, Katrin; Hise, Amy G et al. (2007) Toll-like receptor 2 regulates CXC chemokine production and neutrophil recruitment to the cornea in Onchocerca volvulus/Wolbachia-induced keratitis. Infect Immun 75:5908-15
Hise, Amy G; Daehnel, Katrin; Gillette-Ferguson, Illona et al. (2007) Innate immune responses to endosymbiotic Wolbachia bacteria in Brugia malayi and Onchocerca volvulus are dependent on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM. J Immunol 178:1068-76
Daehnel, K; Gillette-Ferguson, I; Hise, A G et al. (2007) Filaria/Wolbachia activation of dendritic cells and development of Th1-associated responses is dependent on Toll-like receptor 2 in a mouse model of ocular onchocerciasis (river blindness). Parasite Immunol 29:455-65
Lin, Michelle; Carlson, Eric; Diaconu, Eugenia et al. (2007) CXCL1/KC and CXCL5/LIX are selectively produced by corneal fibroblasts and mediate neutrophil infiltration to the corneal stroma in LPS keratitis. J Leukoc Biol 81:786-92
Pearlman, Eric; Gillette-Ferguson, Illona (2007) Onchocerca volvulus, Wolbachia and river blindness. Chem Immunol Allergy 92:254-65

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