angiogenesis in viral immunoinflammatory lesions
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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Angiogenesis in Viral Immunoinflammatory
Lesions
Barry T. RouseUniversity 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
0 5 10 15 20
IL-12 DNAvector DNA
0
1
2
3
4
5
0 5 10 15 20
Expression of IL-12 DNA prior to infection inhibits HSK severity and incidence
Inci
den
ce (
%)
Sev
erit
y
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
+ ve
ctor
Virus
+ IL
-12
Virus
+ ve
ctor
Virus
+ IL
-12
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0
5
10
15
20
An
gio
gen
ic s
cori
ng
0 5 10 15 20
Days post infection
IL-12 DNAIP-10 DNAvector 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- neovascularizationVirus Lesion Mechanism
HHV8 Kaposi’s Sarcoma
Encodes multiple angiogenic proteins
HBV Hepatitis Activates HIF-1a that turns on VEGF promoter
HIV Kaposi’s Sarcoma
Tat activates VEGF-R2
HPV Cervical Cancer Increases VEGF via indirect complex mechanism
HSV Herpetic 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