sirolimus 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

To evaluate and compare the efficacy of rapamycin used topically in a mouse model of herpetic stromal keratitis.. The corneas were infected with herpes simplex virus type-1 strain KOS. Animals were divided into: control (CG), rapamycin (RAPA), cyclosporine (CsA), and dexamethasone (DEXA). The evolution of the disease was assessed clinically and histologically.. On day 10 postinfection (pi), the RAPA group showed only a significantly lower angiogenic development than the CG. On day 14 pi, the treated groups had significantly lower scores for angiogenesis and necrosis than the CG. Also, on day 14 pi, the RAPA and DEXA groups showed significantly lower histopathological scores compared to the CG.. The topical application of 0.05% rapamycin showed greater efficacy than 0.5% cyclosporine and similar efficacy to 0.1% dexamethasone to minimize the immuno-inflammatory process. Also, rapamycin showed early inhibition of the formation of new vessels.

Topics: Administration, Ophthalmic; Animals; Antiviral Agents; Corneal Stroma; Cyclosporine; Dexamethasone; Herpesvirus 1, Human; Keratitis, Herpetic; Mice; Mice, Inbred BALB C; Necrosis; Neovascularization, Pathologic; Severity of Illness Index; Sirolimus; Treatment Outcome

To investigate the effect of human amniotic membrane transplantation (AMT) on T-cell immune response in murine corneas with herpetic stromal keratitis (HSK).. Herpes simplex virus (HSV)-1-infected BALB/c mice with necrotizing HSK were treated with AMT. CD3(+) cell apoptosis was determined in treated corneas and in vitro by flow cytometric analysis using the annexin V/7-AAD system. The effect of interleukin (IL)-2, cyclosporine, rapamycin, or Fas on T-cell survival was measured. Activation phenotype was measured by (3)H-thymidine uptake and flow cytometry (CD25, CD69, major histocompatibility complex class II). Cytokine/chemokine secretion from amniotic membrane (AM)-treated corneas or draining lymph node cells was measured. The immune-modulating capacity of long-term AMT treatment and adoptive transfer of AM-treated splenocytes was tested.. After AMT, HSK and corneal inflammatory cell infiltration improved, and T-lymphocyte apoptosis occurred. T-cell apoptosis was also induced in vitro, independently of rIL-2, cyclosporine, rapamycin, or Fas. AMT-treated corneas and cultured lymphocytes had reduced IL-2, IL-10, IL-12, CRG-2, and CCL-2 content. Long-term AMT treatment decreased the proliferative response and type 1 helper T-cell cytokine level in draining lymph node cells. The improvement in HSK did not persist. Delayed-type hypersensitivity or HSV-1-specific cytotoxicity was not altered. The results suggest that murine HSK improves after AMT through reduced local T-helper cell immune responses by inducing apoptosis in T lymphocytes, independently of passive apoptosis or activation-induced cell death. AM also reduces local T-helper cytokine and chemokine levels but does not result in immune deviation. Immunologic memory against HSV-1 is not affected by AMT, and long-term protection or tolerance is not induced.

Topics: Adoptive Transfer; Amnion; Animals; Apoptosis; CD3 Complex; Cell Culture Techniques; Cell Survival; Coculture Techniques; Corneal Stroma; Cyclosporine; Cytokines; Cytotoxicity, Immunologic; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Herpesvirus 1, Human; Hypersensitivity, Delayed; Keratitis, Herpetic; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Mice, Knockout; Microscopy, Confocal; Sirolimus; Spleen; T-Lymphocytes

Herpes simplex virus infection of mouse corneas can lead to the development of an immunopathological lesion, termed herpetic stromal keratitis (HSK). Such lesions also occur in TCR-transgenic mice backcrossed to SCID (TgSCID) that are unable to mount detectable HSV-specific immune responses. The present study demonstrates that lesion expression in such mice depends on continuous viral replication, whereas in immunocompetent mice, lesions occurred even if virus replication was terminated at 4 days after infection. The continuous replication in TgSCID mice was considered necessary to produce an activating stimulus to CD4(+) T cells that invade the cornea. Lesions in TgSCID were resistant to control by cyclosporin A, but were inhibited by treatment with rapamycin. This result was interpreted to indicate that T cell activation involved a non-TCR-mediated cytokine-driven bystander mechanism. Bystander activation was also shown to play a role in HSK lesions in immunocompetent mice. Accordingly, in immunocompetent DO11.10 mice, lesions were dominated by KJ1.26(+) OVA-specific CD4(+) T cells that were unreactive with HSV. In addition, KJ1.26(+) HSV nonimmune cells parked in ocularly infected BALB/c mice were demonstrable in HSK lesions. These results provide insight for the choice of new strategies to manage HSK, an important cause of human blindness.

Topics: Adoptive Transfer; Animals; Antigens, Viral; CD4-Positive T-Lymphocytes; Cyclosporine; Immunocompetence; Keratitis, Herpetic; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, SCID; Mice, Transgenic; Ovalbumin; Receptors, Antigen, T-Cell; Simplexvirus; Sirolimus