Host Costimulation Control of Herpes Stromal Keratitis in a Model of Syngeneic Orthotopic Corneal Transplantation Grafted in/From 4–1BB,CD28, ICAM–1 and CD80/86 Gene–Deficient Mice

Abstract

Abstract: : Purpose: Herpetic stromal keratitis (HSK) is an autoimmune inflammatory process in corneal stroma resulting from recurrent herpes simplex virus (HSV) type 1 infection. We used the murine syngeneic corneal transplantation model of HSK, grafted in/from 4–1BB, CD28, ICAM–1 and CD80/86 gene–deficient mice, to demonstrate the importance of host costimulation in the development of this disease. Methods: We performed murine syngeneic orthotopic corneal transplantation and HSK was induced by infection with the RE strain of HSV–1. BALB/c–4–1BB^–/–, –CD28^–/– and –WT mice were used as recipients with BALB/c–WT, and –4–1BB^–/–, –CD28^–/– mice serving as syngeneic donors, respectively. In parallel experiments, C57BL/6–ICAM–1^–/–, –CD80^–/–/CD86^–/–, and –WT mice were used as recipients and C57BL/6–WT and –ICAM–1^–/–, –CD80^–/–/CD86^–/– mice serving as donors. The course of HSK was studied clinically and histologically. The eyes were tested for virus replication by standard plaque assay. Flow cytometry was used to analyze the changes in leukocyte population from regional lymph nodes. Results: HSK was prevented 4–1BB^–/– non–grafted cornea and 4–1BB^–/– recipients syn–grafted from WT, whereas CD28^–/– non–grafted cornea and CD28^–/– recipients syn–grafted from WT showed severe HSK, whereas WT recipients syn–grafted from CD28^–/– (CD28^–/– button) revealed a little less score comparison with CD28^–/– recipients syn–grafted from WT. Furthermore, 4–1BB^–/– button showed much higher score compared to 4–1BB^–/– non–grafted cornea and 4–1BB^–/– recipients syn–grafted from WT, but less score comparison with CD28^–/– button. CD80^–/–/CD86^–/– recipients syn–grafted from WT showed pronounced HSK, compared to ICAM–1^–/– recipients syn–grafted from WT and ICAM–1^–/– button and CD80^–/–/CD86^–/– button, which showed no significant differences. Virus clearance was slightly increased in 4–1BB^–/– recipients but not in another groups. Conclusions: Our data suggests that host T cell costimulation control HSK, whereas blocking of donor corneal costimulation remains a little affected. HSK can be effectively prevented by blocking the activities of 4–1BB costimulatory pathway and to a lesser extent by other pathway blockades.

Keywords: herpes simplex virus • cornea: stroma and keratocytes • keratitis