Herpes simplex virus type 1 (HSV-1) induces a destructive inflammatory process referred to as herpes stromal keratitis (HSK). Using a mouse model, we have shown that HSK is regulated by CD4+ T cells through the production of the Th1 cytokines interferon gamma (IFN-) and interleukin 2 (IL-2). The available evidence suggests that the chronic inflammation associated with HSK requires an interaction between CD4+ T cells and antigen presenting cells (APCs) in the infected cornea that maintains the activity of both cells. This reciprocal activation results from signaling through pairs of co-stimulatory molecules that are expressed on CD4+ T cells and APCs, and by the cytokine IL-12 and perhaps a newly discovered homologue IL-23 that are produced by APCs and enhance IFN- production by CD4 T cells. Our studies focus on the co-stimulatory pairs B7-CD28, CD40-CD154, and OX40-OX40L. We propose that signaling through CD40 and OX40L is important to maintain IL-12/IL-23 production by APCs in the infected cornea, and becomes increasingly important in the latter stages of HSK, as the antagonistic effects of IL-10 become more pronounced. We further propose that signaling through CD28, OX40, and IL-12/IL-23 receptors is important to provide CD4+ T cells with the signaling threshold required to maintain Th1 cytokine production, and that this co-stimulation becomes increasingly important as HSK progresses and HSV epitope density in the cornea diminishes. We propose that interference with co-stimulatory interactions at inflammatory sites holds significant therapeutic potential, and will exploit the information gained in these studies to develop cocktails of blocking reagents with optimal efficacy for treating HSK.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY010359-09
Application #
6473078
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Shen, Grace L
Project Start
1993-12-01
Project End
2007-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
9
Fiscal Year
2002
Total Cost
$328,445
Indirect Cost
Name
University of Pittsburgh
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
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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

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