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Angiogenesis in Viral Immunoinflammatory Lesions Barry T. Rouse University of Tennessee Part 1
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The Smokies’ Lost Tribe “Of course we do not have herpes”
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Herpetic Stromal Keratitis An immunoinflammatory reaction in the eye that appears to represent a Type 1 CD4+ T cell mediated reaction in a tissue, the cornea, that normally lacks a vascular system and has been considered as one site of immunological privilege.
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HSV Keratitis in humans Most common infectious cause of blindness in USA At least 400,000 cases About 20% of cases have the immunoinflammatory stromal form Requires chronic treatment and may lead to corneal transplantation
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Pathogenesis of Stromal Keratitis Complex involves multiple humoral and cellular participants Neovascularization a major feature Principal orchestrators of the lesion are CD4+ T cells of the type 1 phenotype
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HSK is caused by CD4+ type 1 T cells but IL-12 expression in the eye prior to HSV infection diminishes rather than exaggerates the lesions. -Lee et. Al. 2002
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0 25 50 75 100 05101520 IL-12 DNA vector DNA 0 1 2 3 4 5 05101520 Expression of IL-12 DNA prior to infection inhibits HSK severity and incidence Incidence (%) Severity Days post infection
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How does the IL-12 effect function? Antiviral effect via IFN- - No Immunosuppression via iNOS - No Modulation of immunity - No Indirect effect on angiogenesis
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-actin IP-10 IFN- MIG IL-10 Gene expression in cornea at day 3 post infection by RT PCR BALB/c GKO naive Virus + vector Virus + IL-12 Virus + vector Virus + IL-12
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0 5 10 15 20 Angiogenic scoring 05101520 Days post infection IL-12 DNA IP-10 DNA vector DNA IL-12 and IP-10 DNA both inhibit ocular angiogenesis IL-12 DNA effect reversed by anti IP-10 + anti MIG
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INTERPRETATION IL-12 expression causes upregulation via IFN- induction of IP- 10 (and MIG). These chemokines bind to heparan sulfate and block the angiogenic effect of FGF. Consequence : inhibited angiogenesis which could be necessary to develop stromal keratitis following virus infection.
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Which molecules are induced in the cornea that can account for HSV-driven neovascularization? Is preventing angiogenesis a logical therapeutic goal for herpetic keratitis?
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Viruses- neovascularization VirusLesionMechanism HHV8Kaposi’s SarcomaEncodes multiple angiogenic proteins HBVHepatitisActivates HIF-1a that turns on VEGF promoter HIVKaposi’s SarcomaTat activates VEGF-R2 HPVCervical CancerIncreases VEGF via indirect complex mechanism HSVHerpetic Stromal Keratitis Mysterious but unraveling
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Productive Infection By HSV Most host mRNA and protein synthesis rapidly shut down A few host proteins are made and secreted. These include IL-1 and IL-6.
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To continue open the Part 2 from Supercourse-Vet htpp://centaur.vri.cz
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