IL-2/Anti–IL-2 Antibody Complex Treatment Inhibits the Development but Not the Progression of Herpetic Stromal Keratitis

Abstract

Interleukin-2 (IL-2) and anti-IL-2 antibody immune complex has recently been shown to expand the naturally occurring pool of CD4+Foxp3+ regulatory T cells (Foxp3+ Tregs). In this report, we showed that administration of IL-2/anti-IL-2 antibody immunocomplex to C57BL/6 mice, prior to corneal herpes simplex virus-1 (HSV-1) infection, significantly increased the pool of Foxp3+ Tregs when measured at early time-points post-infection. Increased numbers of Foxp3+ Tregs on day 2 and day 4 post-infection resulted in a marked reduction in the development of severe HSK. When compared to corneas from the control group, corneas from the immunocomplex-treated group showed a significant reduction in the amount of infectious virus on day 2 but not on day 4 post-infection. Reduced viral load was associated with two-fold increase in NK cell numbers in corneas from the immunocomplex-treated group of mice. Moreover, a dramatic reduction in the influx of CD4 T cells in inflamed corneas was determined on days 7 and 16 post-infection in the immunocomplex-treated group of infected mice. Immunocomplex treatment given on days 5, 6 and 7 post-infection significantly increased Foxp3+ Tregs in draining lymph nodes and in the spleen but failed to reduce the severity of HSK. In terms of the influx of CD4 T cells and granulocytes into inflamed corneas, no significant differences were noted between both groups of mice on day 16 post-infection. Our findings demonstrate that increasing Foxp3+ Tregs early but not late after infection in secondary lymphoid tissues is more efficacious in controlling the severity of HSK.

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

“…Results from many mouse models of herpesvirus infection and immunity have yielded tremendous insights into the protective and immunopathological mechanisms during primary acute infection (46)(47)(48)(49)(50)(51)(52). However, the extrapolation of results from mouse primary herpetic disease to human recurrent herpetic diseases, such as recurrent herpetic stromal keratitis (rHSK), is yet to be proven.…”

Loss of Neurokinin-1 Receptor Alters Ocular Surface Homeostasis and Promotes an Early Development of Herpes Stromal Keratitis

“…A virulent HSV-1 RE Tumpey strain used in the current study was propagated on a monolayer of Vero cells (American Type Culture Collection, Manassas, VA; CCL81) as described previously (14). To carry out an ocular HSV-1 infection, mice were first anesthetized by intra-peritoneal injection of Ketamine (33mg/Kg bodyweight) + Xylazine (20mg/Kg bodyweight) in 0.2 mL PBS.…”

Azacytidine Treatment Inhibits the Progression of Herpes Stromal Keratitis by Enhancing Regulatory T Cell Function

“…Approaches that enhance the function of Treg cells and dampen effector T cells can be effective to limit SK lesion severity (7)(8)(9)(10). In this report, we have explored the novel approach of inhibiting DNA methyltransferase activity using 5-azacytidine (cytosine analog) to limit HSV-induced ocular lesions.…”

“…The lesion is less severe and can even resolve if regulatory T cells (Treg), such as Foxp3 ϩ CD4 T cells, are dominant over the other proinflammatory CD4 T cell subsets (7)(8)(9)(10)(11). Accordingly, therapies aimed at increasing Treg numbers and/or improving their regulatory activity are of high relevance.…”