tacrolimus and Keratitis--Herpetic

The immune privileged nature of the cornea contributes to the favourable outcome in corneal grafts. However, preventive measures are necessary to reduce allograft rejection particular in "high-risk" cases. Although corticosteroids are still a major component of our immunopharmacological armentarium, they might be supplemented by other more specific immunomodulating agents. The spectrum includes agents such as azathioprin, methotrexate or more specific calcineurin inhibitors affecting T-cells (cyclosporin A, FK506) and highly selective monoclonal antibodies directed against T-cell subpopulations and other targets. In order to better evaluate the risks and benefit of these agents, the properties of established and forthcoming agents are presented. In addition, this review attempts to address some new concepts of tolerance induction following penetrating keratoplasty.

Topics: Adjuvants, Immunologic; Adrenal Cortex Hormones; Animals; Antiviral Agents; Azathioprine; Clinical Trials as Topic; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Keratitis, Herpetic; Keratoplasty, Penetrating; Methotrexate; Mice; Multicenter Studies as Topic; Mycophenolic Acid; Pilot Projects; Prospective Studies; Risk Factors; Sirolimus; Tacrolimus

Herpes simplex virus type-1 (HSV-1) is a leading cause of neurotrophic keratitis, characterized by decreased or absent corneal sensation due to damage to the sensory corneal innervation. We previously reported the elicited immune response to infection contributes to the mechanism of corneal nerve regression/damage during acute HSV-1 infection. Our aim is to further establish the involvement of infiltrated macrophages in the mechanism of nerve loss upon infection.. Macrophage Fas-Induced Apoptosis (MAFIA) transgenic C57BL/6 mice were systemically treated with AP20187 dimerizer or vehicle (VEH), and their corneas, lymph nodes, and blood were assessed for CD45+CD11b+GFP+ cell depletion by flow cytometry (FC). Mice were ocularly infected with HSV-1 or left uninfected. At 2, 4, and/or 6 days post infection (PI), corneas were assessed for sensitivity and harvested for FC, nerve structure by immunohistochemistry, viral content by plaque assay, soluble factor content by suspension array, and activation of signaling pathways by Western blot analysis. C57BL6 mice were used to compare to the MAFIA mouse model.. MAFIA mice treated with AP20187 had efficient depletion of CD45+CD11b+GFP+ cells in the tissues analyzed. The reduction of CD45+CD11b+GFP+ cells recruited to the infected corneas of AP20187-treated mice correlated with preservation of corneal nerve structure and function, decreased protein concentration of inflammatory cytokines, and decreased STAT3 activation despite no changes in viral content in the cornea compared to VEH-treated animals.. Our results suggest infiltrated macrophages are early effectors in the nerve regression following HSV-1 infection. We propose the neurodegeneration mechanism involves macrophages, local up-regulation of IL-6, and activation of STAT3.

Topics: Animals; Blotting, Western; Cornea; Disease Models, Animal; Flow Cytometry; Herpesvirus 1, Human; Immunohistochemistry; Interleukin-6; Keratitis, Herpetic; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Degeneration; Receptor, Macrophage Colony-Stimulating Factor; STAT3 Transcription Factor; Tacrolimus; Trigeminal Nerve; Trigeminal Nerve Diseases; Viral Plaque Assay

To investigate the effectiveness of topical tacrolimus treatment on herpetic stromal keratitis (HSK) in a rat model.. The development of HSK was monitored for 14 days after the inoculation of rats with herpes simplex type 1 virus. Rats that developed HSK were divided into four groups as follows: (1) topical antiviral treatment (control), (2) topical antiviral and 1% prednisolone acetate, (3) topical antiviral and 0.03% tacrolimus ointment, and (4) topical antiviral plus 0.1% tacrolimus ointment. After 14 days of treatment, the severity levels of HSK were scored and compared with the levels before the treatment. The expression of CD3, CD4, and CD8 was evaluated by flow cytometry. The development of the disease was evaluated clinically and histologically.. Significant improvement in vascularization was observed in the groups with the drug treatment in addition to the antiviral agent (P<0.05), but there was no obvious difference within groups 2, 3, and 4 in the vascularization severity. The regression of corneal edema was 8.05%±6% in group 1, 25.17%±14.55% in group 2 (P=0.01), 36.40%±21.69% in group 3 (P=0.03), and 46.39%±14.96% in group 4 (P=0.00). A significant decrease in the number of inflammatory cells in the groups with the drug treatment was evaluated by immunohistochemical staining and confirmed by flow cytometry analysis.. Topical tacrolimus treatment caused a significant decrease in corneal vascularization accompanied by a lower number of inflammatory cells in the experimental HSK corneal edema model. Therefore, topical tacrolimus has the potential to be used in the treatment of HSK.

Topics: Administration, Topical; Animals; CD3 Complex; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Corneal Diseases; Corneal Stroma; Disease Models, Animal; Eye Infections, Viral; Flow Cytometry; Glucocorticoids; Herpesvirus 1, Human; Immunosuppressive Agents; Keratitis, Herpetic; Ophthalmic Solutions; Prednisolone; Prospective Studies; Rats; Rats, Wistar; Tacrolimus