Transcript Slide 1
Angiogenesis in Viral Immunoinflammatory Lesions Barry T. Rouse University of Tennessee Part 1 The Smokies’ Lost Tribe “Of course we do not have herpes” 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. 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 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 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 Expression of IL-12 DNA prior to infection inhibits HSK severity and incidence 5 vector DNA IL-12 DNA 4 75 3 50 2 25 1 0 0 0 5 10 15 20 0 5 Days post infection 10 15 20 Severity Incidence (%) 100 How does the IL-12 effect function? • • • • Antiviral effect via IFN- - No Immunosuppression via iNOS - No Modulation of immunity - No Indirect effect on angiogenesis Gene expression in cornea at day 3 post infection by RT PCR BALB/c IL-10 IFN- IP-10 MIG b-actin GKO IL-12 and IP-10 DNA both inhibit ocular angiogenesis Angiogenic scoring 20 vector DNA IP-10 DNA IL-12 DNA 15 10 5 0 0 5 10 15 20 Days post infection IL-12 DNA effect reversed by anti IP-10 + anti MIG 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. • Which molecules are induced in the cornea that can account for HSV-driven neovascularization? • Is preventing angiogenesis a logical therapeutic goal for herpetic keratitis? Viruses- neovascularization Virus Lesion HHV8 Kaposi’s Sarcoma Encodes multiple angiogenic proteins Hepatitis Activates HIF-1a that turns on VEGF promoter HBV Mechanism HIV Kaposi’s Sarcoma Tat activates VEGF-R2 HPV Cervical Cancer HSV Herpetic Stromal Keratitis Increases VEGF via indirect complex mechanism Mysterious but unraveling 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. • To continue open the Part 2 • from Supercourse-Vet • htpp://centaur.vri.cz