Role of IL-12 in regulating Herpes simplex keratitis (HSK)

Abstract

Abstract: : Purpose: Herpes Simplex Keratitis (HSK) is regulated by the Th1 cytokine interferon gamma (IFN-γ). IFN-γ production is regulated by IL-12, which consists of a p40 chain and a p35 chain. Recently a second molecule called IL-23 (consisting of the IL-12 p40 chain and a p19 chain) was also shown to regulate IFN-γ production in memory T cells. The purpose of this study was to investigate the contribution of IL-12 to HSK. Methods: The corneas of Balb/c mice were infected with RE HSV-1 and monitored for IL-12 production by RT-PCR. Experimental groups included mice that were depleted of T cells by injection of monoclonal antibodies (mAb) to CD4 and CD8, T cell depleted mice that received a subconjunctival (s.c.) injection of an agonist mAb to CD40, or mice with targeted disruption of the gene for IL-12 p35. Results: IL-12 p40 message was produced in the infected cornea early (at the time of HSV-1 epithelial lesions) and again later (during the development of HSK). The early IL-12 p40 expression was not affected by T cell depletion, whereas the later production was markedly reduced in T cell depleted mice. Late IL-12 p40 mRNA expression in T cell-depleted mice was augmented by s.c. injection of anti-CD40 mAb. The IL-12 p40 chain is shared by IL-12 and the recently described IL-23. Injection of wild type mice with anti-IL-12 p40 mAb abrogated the development of HSK. In contrast, IL-12 p35 knockout mice developed HSK normally for the first two weeks after infection, but then the inflammation subsided. Conclusion: IL-12 is dispensable during the early stages of HSK (perhaps due to an overlapping role of IL-23), but IL-12 is required for HSK progression beyond two weeks. We hypothesize that the differential requirement during the early and late stages of HSK might reflect the involvement of HSV-1 reactive memory cells (early) and bystander activated T cells at later times when the HSV epitope density is reduced in the cornea.

Keywords: 425 herpes simplex virus • 435 immunomodulation/immunoregulation • 380 cytokines/chemokines