ovalbumin and Keratitis--Herpetic

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

Stromal keratitis is an immunopathologic consequence of herpes simplex virus (HSV) infection of the cornea. The lesion is immunopathologic, but the identities of molecules that drive the reaction remain unresolved. To exclude viral antigen recognition as a necessary step in the disease process, ocular HSV infection was followed in Tg-RAG mice (OVA-TCR transgenic mice crossed to RAG2-deficient mice) whose limited T-cell repertoire did not include immune responsiveness to HSV.. Mice with T-cell specificity to OVA peptide (Tg-RAG mice) as well as control DO11.10 and BALB/c mice were infected with HSV on the scarified cornea and subjected to clinical, histologic, and immunologic analysis. To evaluate involvement of OVA-specific CD4+ T cells in lesion development in Tg-RAG mice, monoclonal antibody to CD4+ T cells was used for in vivo CD4+ T-cell depletion.. Tg-RAG mice were capable of eliciting ocular lesions in the absence of detectable reactivity to viral antigens. Lesion manifestation in Tg-RAG mice was CD4+ T-cell dependent and the cellular infiltrates and their inflammatory products in the HSV-infected cornea were comparable to similarly infected BALB/c and DO11.10 mice.. The authors conclude that mechanisms other than viral antigen recognition, and hence molecular mimicry, are at play and are sufficient to cause HSV-induced stromal keratitis. The data imply a significant role for non-virus-specific CD4+ T cells that could become activated by an inflammatory milieu consisting of enhanced accessory molecules and proinflammatory cytokines in the cornea.

Topics: Animals; CD4-Positive T-Lymphocytes; Corneal Stroma; Enzyme-Linked Immunosorbent Assay; Herpesvirus 1, Human; Immunoenzyme Techniques; Immunoglobulin G; Interferon-gamma; Keratitis, Herpetic; Lymphocyte Activation; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Mice, Transgenic; Molecular Mimicry; Ovalbumin; Reverse Transcriptase Polymerase Chain Reaction; RNA