UV radiation, skin cancer and immune suppression

The possible applications of this research

Sophie Harris & Lisa Joseph

The evidence Walterscheid et al (2006)

• Serotonin and UCA share 5-HT2A receptor

• Activation of immune suppression– How? (Woodward et al 2006)

– What is the role of the 5-HT1 receptor?

• Induction of skin cancer– Via 5-HT2A?

The story so far...• 50% mice injected with

PAF receptor antagonist• 50% mice injected with

control (PBS)• All mice exposed to same

dose UVB• PAF receptor antagonism

prevents tumour development (p<0.001)

• Similar with ketanserin (5-HT2R antagonist)

The future

• Therapeutic use of PAF and 5-HT2A receptor antagonists– Prevention– Halt progression

• Clinical application for high-risk individuals:– Psoriasis (PUVA) patients– Renal transplant patient– Individuals with fair skin

Psoriasis

• PUVA (Psoralen plus UVA)– Repeated treatments

• Increases risk squamous cell carcinoma significantly (Stern RS et al 1998)

• Balance risk vs benefits• Use a PAF/5-HT2A receptor

antagonist to reduce risk?

Renal transplant recipients (RTRs)

• Lifelong immunosuppression• Nonmelanoma skin cancer

– SCC– Increased aggression and metastasis– Linked to UVR and immunosuppression (HPV)

(Queille S et al 2006)

• Use a PAF/5-HT2A receptor antagonist to reduce risk?

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)

Fair skin

• Sensitivity to sunburn associated with increasedsusceptibility to UV-induced immunosuppression– Type I/II skin 2/3 times more susceptible than type

III/IV skin (Kelly DA et al. 2000)

– Role in increased risk of skin cancer?

• Use a PAF/5-HT2A receptor antagonist to reduce risk?

Protection• Oestrogen receptor Widyarini et al 2006

– Via antioxidants equol and metallothionein– Different needs photoprotection males vs females– Topical equol reduces carcinogenesis after chronic

irradiation

Infection and UVR-induced immunosuppression

• UVR and immune response widely studied in animal models (Norval M et al 2006)

• UVR suppresses Th1 cytokine response– Increased severity and reduced ability to clear

infections– Decreased resistance to infection/re-infection– Increased viral reactivation from latency– Increases viral oncogenicity

Human Infections• HSV• HPV

– UVR promotes development of SCC’s– Increase in active HPV infection in cervix in

summer months (Hrushesky WJ et al. 2005)

• HIV– UVR raises HIV skin expression (Breuer-McHam et al 2001)

– CD4 cell counts reduce in summer• Antagonists role in preventing/fighting infection?

• UVR and vaccinations?

UVR and the eye

Tissue Acute effect Chronic effectConjunctiva Photoconjunctivitis

Chemosis (swelling)Pinguecula (local degenerationDyskeratosisIntraepithelial neoplasia (e.g conjunctival scc’s)

Cornea PhotokeratitisEndothelial damage Reactivation of latent HSV

Climatic droplet kaeratopathyPterygiumEndothelial changes

Lens Anterior subcapsular opacities

Age related cataract

Norval M et al. 2007

• Role of UVR-induced immunosuppression in ocular diseases?

Limitations of this approach

• 5-HT2A widely expressed receptor– Brain– Platelets– Smooth muscle

• 5-HT2A antagonists– Atypical antipsychotics– Ketanserin

• Unwanted effects• Pharmacokinetics

What about the 5-HT1 receptor?

• Zolmitriptan (5-HT1 agonist) blocks cis-UCA-induced immune suppression Walterscheid et al 2006

• 5-HT1 agonists– Cerebral vasoconstriction– Migraine

• New therapeutic use?

Inducing immunosuppression as a therapeutic strategy

• Benefit in psoriasis– Exogenous cis-UCA or 5-HT2A agonist instead of

light therapy?

• Autoimmune conditions:– Possible benefit in diseases associated with Th1

activity? e.g diabetes and multiple sclerosis (Posonby

AL et al. 2002)

Is it all physiological?

If all else fails…..drink green tea!!