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Transcript
Inhalation exposure to transition metals can facilitate sensitization to an innocuous protein antigen Fraleigh NL, S Lefebvre, S Khurana, B Ross and SA Ritz 1 Inhalation Tolerance • Respiratory tract is exposed to various antigens • Inhalation tolerance results in the active suppression of responses towards harmless antigens • ~15% of the industrialized world has an allergy Diaz-Sanchez Det al. 1996, Diaz-Sanchez D et al. 1997, Diaz-Sanchez Det al. 1999, Rumold R et al. 2001, Swirski FK et al. 2002, Whitek MJ et al.. 2002, Steerenberg PA et al. 2003, Steerenberg PA et al. 2004, Steerenberg PA et al. 2005, Riedl et al. 2005 Image from Wikipedia Commons 2 Health and Economic Effects In 2008, air pollution is estimated to be responsible for: ◦ ~21 000 premature deaths ◦ ~11 000 hospital admissions ◦ ~92 000 ER visits ◦ ~620 000 MD visits ◦ ~$8B in economic costs 3 Particulate Matter • Particulate matter is the solid portion of air pollution • Exacerbates cardiovascular and respiratory disease in those at risk and causes inflammation • Dependent upon local environment • Sudbury Particulate Matter contains nickel – Nickel induces inflammation and the production of reactive oxygen species Frampton MW et al. 1999, Ritz SA et al. 2002, Wallenborn JG et al. 2009, Riley MR et al. 2003 4 Study Rationale • Nickel may be able to act as an adjuvant and induce allergic sensitization • Mice will be exposed to a harmless antigen (OVA) with or without Ni3S2, and inflammatory and immune responses assessed – Hallmarks of allergic responses: eosinophilia, IgE, Th2 cytokines 5 Methodology X daily instillation of metals (i.n.) (or saline control) 0 1 10 48h daily OVA aerosolization (or saline control) Image from Charles River criver.com 6 Airway Inflammation 250 ng Ni3S2 OVA/saline Ni (250 ng)/OVA 7 Total Number of WBC in BAL of Acutely Treated Balb/c Mice 1.4e+6 1.2e+6 8.0e+5 6.0e+5 4.0e+5 2.0e+5 Treatment Groups Ni(10 00)/O VA Ni(25 0)/O VA Ni(50 )/OV A OVA /salin e 0.0 Naiv e Co ntrol White Blood Cells (cells/mL) 1.0e+6 8 Total Number of Eosinophils in Acutely Treated Balb/c Mice 20000 Number of Eosinophils (cells/mL) 15000 10000 5000 0 Naive Control OVA/saline Ni(50 ng)/OVA Ni(250)/OVA Ni(1000)/OVA Treatment Groups 9 Methodology X daily instillation of metals (i.n.) (or saline control) 0 1 10 5 weeks 72h daily OVA aerosolization (or saline control) challenge with aerosolized OVA 10 Total Number of Cells in BAL of Rechallenged Balb/c Mice 1.4e+6 1.0e+6 8.0e+5 6.0e+5 4.0e+5 2.0e+5 Treatment Groups Ni ( 1 000) /O VA R VA R 50)/O Ni ( 2 0)/O VA R Ni ( 5 OVA /salin eR 0.0 Naiv e c on trol R Total Number of Cells (cells/mL) 1.2e+6 11 Number of Eosinophils in BAL of Rechallenged Balb/c Mice 12000 8000 6000 4000 2000 Treatment Groups Ni/O VA 1000 ng Ni/O VA 250 ng Ni/O VA 50 n g OVA /salin e 0 Naiv e Co ntrol Eosinophils (cells/mL) 10000 12 • Histological processing of lungs • OVA-specific Immunoglobin ELISA • Repeat the experiment with a dose reflecting the results obtained from the pilot study 13 Take Home Message • Nickel is able to induce an inflammatory response leading to increased levels of inflammation • Groups that were treated with low doses of Ni and rechallenged with OVA had increased levels of eosinophilia • Low doses of Ni may act as an adjuvant and elicit allergic sensitization to another antigen 14 Acknowledgements • I would like to thank the members of Team Ritz for all of their help and support – – – – Dr. Stacey Ritz Sandhya Khurana Sebastien Lefebvre Sarah White • Manel Jordana Lab at McMaster University • Joe Eibl and NOSM lab • CIHR Team in Gender Environment and Health • NOSM/NOSM FA Research