Herpes simplex virus 1 (HSV-1) infection of the eye can result in stromal keratitis (SK), a chronic immunoinflammatory lesion and a significant cause of human blindness. A key to controlling the severity of SK lesions is to identify cell and molecular events responsible for tissue damage and to modulate their function. This report evaluates the role of LT-α, a proinflammatory cytokine that could be involved in mediating tissue damage during SK, and the use of a mAb that targets it. We show that in response to HSV infection, LT-α is upregulated and derived from proinflammatory cells such as neutrophils, γδ-T cells and T cells. We also show that LT-α, when expressed as LT-α3 (soluble) or LT-α1β2 (membrane bound), has a proinflammatory role in vitro in a corneal cell line. Moreover, mAb treatment during the clinical phase of the disease, which specifically targets cells expressing LT-α1β2 and its soluble version LT-α3, significantly attenuated SK lesions. In these mice, corneas expressed reduced levels of proinflammatory molecules, chemokines, and infiltration of proinflammatory cells when compared to control mice. However, treatment in vivo with a mutant version of the mAb, which only binds to LT-α3 did not decrease SK scores, indicating that the inhibitory activity may be dependent on targeting cells expressing LT-α1β2. We discuss our results in terms of the potential therapeutic value of managing SK in a clinical setting with a mAb targeting cells that express LT-α1β2.
- Copyright © 2013 by The American Association of Immunologists, Inc.