Further Work


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  • Further Work

    1. 1. UV radiation, skin cancer and immune suppression The possible applications of this research Sophie Harris & Lisa Joseph
    2. 2. The evidence Walterscheid et al (2006) <ul><li>Serotonin and UCA share 5-HT 2A receptor </li></ul><ul><li>Activation of immune suppression </li></ul><ul><ul><li>How? (Woodward et al 2006) </li></ul></ul><ul><ul><li>What is the role of the 5-HT 1 receptor? </li></ul></ul><ul><li>Induction of skin cancer </li></ul><ul><ul><li>Via 5-HT 2A ? </li></ul></ul>
    3. 3. The story so far... <ul><li>50% mice injected with PAF receptor antagonist </li></ul><ul><li>50% mice injected with control (PBS) </li></ul><ul><li>All mice exposed to same dose UVB </li></ul><ul><li>PAF receptor antagonism prevents tumour development (p<0.001) </li></ul><ul><li>Similar with ketanserin (5-HT 2 R antagonist) </li></ul>
    4. 4. The future <ul><li>Therapeutic use of PAF and 5-HT 2A receptor antagonists </li></ul><ul><ul><li>Prevention </li></ul></ul><ul><ul><li>Halt progression </li></ul></ul><ul><li>Clinical application for high-risk individuals: </li></ul><ul><ul><li>Psoriasis (PUVA) patients </li></ul></ul><ul><ul><li>Renal transplant patient </li></ul></ul><ul><ul><li>Individuals with fair skin </li></ul></ul>
    5. 5. Psoriasis <ul><li>PUVA (Psoralen plus UVA) </li></ul><ul><ul><li>Repeated treatments </li></ul></ul><ul><li>Increases risk squamous cell carcinoma significantly (Stern RS et al 1998) </li></ul><ul><li>Balance risk vs benefits </li></ul><ul><li>Use a PAF/5-HT 2A receptor antagonist to reduce risk? </li></ul>
    6. 6. Renal transplant recipients (RTRs) <ul><li>Lifelong immunosuppression </li></ul><ul><li>Nonmelanoma skin cancer </li></ul><ul><ul><li>SCC </li></ul></ul><ul><ul><li>Increased aggression and metastasis </li></ul></ul><ul><ul><li>Linked to UVR and immunosuppression (HPV) (Queille S et al 2006) </li></ul></ul><ul><li>Use a PAF/5-HT 2A receptor antagonist to reduce risk? </li></ul>
    7. 7. Skin Type Reaction to sun exposure I Always burns, never tans II Usually burns, rarely tans III Seldom burns, gradually tans IV Rarely burns, tans easily V Very rarely burns, tans very easily (pigmented) VI Never burns, tans very easily (deeply pigmented)
    8. 8. Fair skin <ul><li>Sensitivity to sunburn </li></ul><ul><li>associated with increased </li></ul><ul><li>susceptibility to UV-induced immunosuppression </li></ul><ul><ul><li>Type I/II skin 2/3 times more susceptible than type III/IV skin (Kelly DA et al. 2000) </li></ul></ul><ul><ul><li>Role in increased risk of skin cancer? </li></ul></ul><ul><li>Use a PAF/5-HT 2A receptor antagonist to reduce risk? </li></ul>
    9. 9. Protection <ul><li>Oestrogen receptor Widyarini et al 2006 </li></ul><ul><ul><li>Via antioxidants equol and metallothionein </li></ul></ul><ul><ul><li>Different needs photoprotection males vs females </li></ul></ul><ul><ul><li>Topical equol reduces carcinogenesis after chronic irradiation </li></ul></ul>
    10. 10. Infection and UVR-induced immunosuppression <ul><li>UVR and immune response widely studied in animal models (Norval M et al 2006) </li></ul><ul><li>UVR suppresses Th1 cytokine response </li></ul><ul><ul><li>Increased severity and reduced ability to clear infections </li></ul></ul><ul><ul><li>Decreased resistance to infection/re-infection </li></ul></ul><ul><ul><li>Increased viral reactivation from latency </li></ul></ul><ul><ul><li>Increases viral oncogenicity </li></ul></ul>
    11. 11. Human Infections <ul><li>HSV </li></ul><ul><li>HPV </li></ul><ul><ul><li>UVR promotes development of SCC’s </li></ul></ul><ul><ul><li>Increase in active HPV infection in cervix in summer months (Hrushesky WJ et al. 2005) </li></ul></ul><ul><li>HIV </li></ul><ul><ul><li>UVR raises HIV skin expression (Breuer-McHam et al 2001) </li></ul></ul><ul><ul><li>CD4 cell counts reduce in summer </li></ul></ul><ul><li>Antagonists role in preventing/fighting infection? </li></ul><ul><li>UVR and vaccinations ? </li></ul>
    12. 12. UVR and the eye Norval M et al. 2007 <ul><li>Role of UVR-induced immunosuppression in ocular diseases? </li></ul>Tissue Acute effect Chronic effect Conjunctiva Photoconjunctivitis Chemosis (swelling) Pinguecula (local degeneration Dyskeratosis Intraepithelial neoplasia (e.g conjunctival scc’s) Cornea Photokeratitis Endothelial damage Reactivation of latent HSV Climatic droplet kaeratopathy Pterygium Endothelial changes Lens Anterior subcapsular opacities Age related cataract
    13. 13. Limitations of this approach <ul><li>5-HT 2A widely expressed receptor </li></ul><ul><ul><li>Brain </li></ul></ul><ul><ul><li>Platelets </li></ul></ul><ul><ul><li>Smooth muscle </li></ul></ul><ul><li>5-HT 2A antagonists </li></ul><ul><ul><li>Atypical antipsychotics </li></ul></ul><ul><ul><li>Ketanserin </li></ul></ul><ul><li>Unwanted effects </li></ul><ul><li>Pharmacokinetics </li></ul>
    14. 14. What about the 5-HT 1 receptor? <ul><li>Zolmitriptan (5-HT 1 agonist) blocks cis -UCA-induced immune suppression Walterscheid et al 2006 </li></ul><ul><li>5-HT 1 agonists </li></ul><ul><ul><li>Cerebral vasoconstriction </li></ul></ul><ul><ul><li>Migraine </li></ul></ul><ul><li>New therapeutic use? </li></ul>
    15. 15. Inducing immunosuppression as a therapeutic strategy <ul><li>Benefit in psoriasis </li></ul><ul><ul><li>Exogenous cis -UCA or 5-HT 2A agonist instead of light therapy? </li></ul></ul><ul><li>Autoimmune conditions: </li></ul><ul><ul><li>Possible benefit in diseases associated with Th1 activity? e.g diabetes and multiple sclerosis (Posonby AL et al. 2002) </li></ul></ul>
    16. 16. <ul><li>Is it all physiological? </li></ul><ul><li>If all else fails…..drink green tea!! </li></ul>