Herpes stromal keratitis (HSK) in the mouse is regulated by CD4+ T lymphocytes when activated by Langerhans cells (LC) in the infected cornea. The PI proposed that a three-step interaction of CD+4 T cells with LC leads to HSK: 1) T cell receptor ligation by viral peptides that are bound to MHC class II molecules on LC; 2) binding of CD40 ligand (CD40L) on partially activated T cells to CD40 on LC induces LC expression of the costimulatory molecule B7-1 and the cytokine IL-12; 3) B7-1 binding to CD28 in the presence of IL-12 induces Th1 cytokine production by the CD4+ T cells. He proposes two specific aims to test this hypothesis.
Specific aim 1 will expand on preliminary finding suggesting that B7-2 costimulation is requires for induction of the CD4+ T cell response to HSV in the lymph nodes, whereas B7-1 costimulation is required for re- stimulation of the CD4 + cells in the infected cornea. He will attempt to alter the inductive and effector phases of the CD4+ T cell response to HSV through intraperitoneal (i.p.) and subconjunctival (s.c.) Injection, respectively, of monoclonal antibodies (mAb) to B7-1, B7-2, and CTLA4. Cytokine production in the lymph nodes and corneas, and HSK will be monitored in these mice. In addition, the susceptibility to HSK of mice that are genetically deficient in B7-1, B7-2, and CD28 will be tested, and the relative importance of costimulation through B7-1 and B7-2 binding to CD28 in the lymph nodes and cornea will be determined through a series of adoptive transfer studies.
Specific Aim 2 will determine the importance of T cells and the CD40L in regulating B7-1 expression and IL-12 production by LC in infected corneas, as well as the role of CD40L/CD40 interaction and IL-12 production in HSK. These vivo studies will involve blocking experiments with mAb to CD40L and IL-12, and adoptive transfer studies with mice that are genetically deficient in CD40L. These studies will define the costimulatory requirement for CD4+ T cell activation in the HSV-1-infected cornea, and possibly provide important new avenues for intervention in HSK.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY010359-05
Application #
2471219
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1993-12-01
Project End
2002-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
5
Fiscal Year
1998
Total Cost
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
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

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