title: Anti-IL-17 therapy restricts and reverses late-term corneal allorejection.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Saint Louis University School of Medicine, St. Louis, MO 63104.
authors.forename: Xiao-Tang
authors.initials: XT
authors.lastname: Yin
authors.affiliation: Department of Ophthalmology, Saint Louis University School of Medicine, St. Louis, MO 63104.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zobell
authors.affiliation: Department of Ophthalmology, Saint Louis University School of Medicine, St. Louis, MO 63104.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Jarosz
authors.affiliation: Department of Ophthalmology, Saint Louis University School of Medicine, St. Louis, MO 63104 pstuart2@slu.edu.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Stuart
mesh_terms: D000208:Acute Disease; D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D003315:Cornea / Q000276:immunology* / Q000473:pathology; D016039:Corneal Transplantation; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; C098680:Il17a protein, mouse; D020381:Interleukin-17