Corneal inflammation is a significant cause of visual morbidity. Inflammation can be induced by a variety of infectious and noninfectious agents.The corneal stromal inflammation associated with HSV-1 infections is the leading infectious cause of blindness in this country. The KOS and RE strains of Herpes simplex virus (HSV-1) have been found to induce markedly different types of inflammation in the corneas of A/J mice.CD8 T lymphocytes play a critical role in the inflammation induced in the cornea by KOS HSV-1, which is characterized primarily by a mononuclear infiltrate. RE HSV-1 infection leads to a predominantly neutrophilic infiltration, in which CD4 T lymphocytes play an essential role. Since leukocyte extravasation and migration into inflammatory sites appear to be controlled by local expression of cytokines and adhesion molecules, the involvement of these molecules will be investigated in the corneal inflammation induced in mouse corneas by the KOS and RE strains of HSV-1. These studies will involve both in vivo and in vitro assays for leukocyte extravasation and migration. The cornea is an ideal tissue in which to conduct these studies becaused it is avascular.Thus, leukocytes that extravasate from the vessels at the peripheral margin of the cornea must migrate through several millimeters of tissue to reach the site of infection in the central cornea. This permits one to separately study the processes of extravasation and migration through the extracellular matrix of the corneal stroma. The involvement of various cytokines in the extravasion and migration of different populations of inflammatory cells into KOS- and RE HSV-1-infected corneas will be tested. This will be done in vivo by treatment of infected mice with monoclonal antibodies capable of neutralizing various cytokines, and then following the progress of the inflammatory response. The same antibodies will be employed that are need to block migration of leukocytes into infected corneal buttons, an assay recently developed in our laboratory. Similar studies will be conducted with antibodies to adhesion molecules and other inhibitors of the interaction of adhesion molecules with their ligands on vascular endothelium and extracellular matrix proteins.These studies may lead to the development of new means of intervening in the blinding inflammatory disease that is associated with HSV-1 corneal infections. These studies may also provide a useful paradigm for studying other inflammatory diesases that occur in the cornea as well as other tissues.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010359-02
Application #
2164173
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1993-12-01
Project End
1997-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Kuffova, Lucia; Knickelbein, Jared E; Yu, Tian et al. (2016) High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection. Invest Ophthalmol Vis Sci 57:1578-87
Buela, Kristine-Ann G; Hendricks, Robert L (2015) Cornea-infiltrating and lymph node dendritic cells contribute to CD4+ T cell expansion after herpes simplex virus-1 ocular infection. J Immunol 194:379-87
Knickelbein, Jared E; Buela, Kristine-Ann; Hendricks, Robert L (2014) Antigen-presenting cells are stratified within normal human corneas and are rapidly mobilized during ex vivo viral infection. Invest Ophthalmol Vis Sci 55:1118-23
Yun, Hongmin; Rowe, Alexander M; Lathrop, Kira L et al. (2014) Reversible nerve damage and corneal pathology in murine herpes simplex stromal keratitis. J Virol 88:7870-80
Medina, Carlos A; Rowe, Alexander M; Yun, Hongmin et al. (2013) Azithromycin treatment increases survival of high-risk corneal allotransplants. Cornea 32:658-66
St Leger, Anthony J; Jeon, Sohyun; Hendricks, Robert L (2013) Broadening the repertoire of functional herpes simplex virus type 1-specific CD8+ T cells reduces viral reactivation from latency in sensory ganglia. J Immunol 191:2258-65
Rowe, A M; St Leger, A J; Jeon, S et al. (2013) Herpes keratitis. Prog Retin Eye Res 32:88-101
Frank, Gregory M; Buela, Kristine-Ann G; Maker, Dawn M et al. (2012) Early responding dendritic cells direct the local NK response to control herpes simplex virus 1 infection within the cornea. J Immunol 188:1350-9
Swamynathan, Sudha; Buela, Kristine-Ann; Kinchington, Paul et al. (2012) Klf4 regulates the expression of Slurp1, which functions as an immunomodulatory peptide in the mouse cornea. Invest Ophthalmol Vis Sci 53:8433-46
Frank, Gregory M; Divito, Sherrie J; Maker, Dawn M et al. (2010) A novel p40-independent function of IL-12p35 is required for progression and maintenance of herpes stromal keratitis. Invest Ophthalmol Vis Sci 51:3591-8

Showing the most recent 10 out of 27 publications