Anti-IL-17 therapy restricts and reverses late-term corneal allorejection.

Corneal allograft rejection has been described as a Th1-mediated process involving IFN-γ production. However, recent evidence also implicated IL-17 as being involved in acute corneal allograft responses. Our data support that IL-17 is involved in early acute corneal allograft acceptance. However, we decided to extend these studies to include a later phase of rejection in which there is a peak of IL-17 production that is >15-fold higher than that seen during acute rejection and occurs >45 d postengraftment at the onset of late-term rejection. We demonstrate that neutralizing IL-17A at this time significantly reduced corneal graft rejection. Surprisingly, when corneal grafts that are undergoing this later phase of rejection are treated with anti-IL-17A, there is a reversal of both opacity and neovascularization. Compared with the early phase of rejection, the cellular infiltrate is significantly less, with a greatly reduced presence of Gr-1(+) neutrophils and a relative increase in CD4(+) T cells and macrophages. We went on to identify that the cells expressing IL-17 were CD4(+) IL-17(+) T cells and, somewhat surprisingly, IL-17(+) F4/80(+) macrophages within the rejecting corneal allografts. Taken together, these findings describe a distinct late phase of corneal allograft rejection that is likely mediated by Th17 cells; therapeutic neutralization of IL-17A reverses this rejection. This further suggests that IL-17 might serve as an excellent therapeutic target to reduce this form of corneal allograft rejection.

Mice with mutations in Fas and Fas ligand demonstrate increased herpetic stromal keratitis following corneal infection with HSV-1.

HSV-1 infection of the cornea leads to a potentially blinding immunoinflammatory lesion of the cornea, termed herpetic stromal keratitis. It has also been shown that one of the factors limiting inflammation of the cornea is the presence of Fas ligand (FasL) on corneal epithelium and endothelium. In this study, the role played by FasL expression in the cornea following acute infection with HSV-1 was determined. Both BALB/c and C57BL/6 (B6) mice with HSV-1 infection were compared with their lpr and gld counterparts. Results indicated that mice bearing mutations in the Fas Ag (lpr) displayed the most severe disease, whereas the FasL-defective gld mouse displayed an intermediate phenotype. It was further demonstrated that increased disease was due to lack of Fas expression on bone marrow-derived cells. Of interest, although virus persisted slightly longer in the corneas of mice bearing lpr and gld mutations, the persistence of infectious virus in the trigeminal ganglia was the same for all strains infected. Further, B6 mice bearing lpr and gld mutations were also more resistant to virus-induced mortality than were wild-type B6 mice. Thus, neither disease nor mortality correlated with viral replication in these mice. Collectively, the findings indicate that the presence of FasL on the cornea restricts the entry of Fas(+) bone marrow-derived inflammatory cells and thus reduces the severity of HSK.