1 / 12

Ronald L. Rabin, M.D. CBER/FDA Office of Vaccine Research and Review Laboratory of Immunobiochemistry

Ronald L. Rabin, M.D. CBER/FDA Office of Vaccine Research and Review Laboratory of Immunobiochemistry. Respiratory syncytial virus (RSV): an environmental factor in the pathogenesis of asthma and allergy. Asthma: a classic example of interaction between genetics and environment.

tanginika
Download Presentation

Ronald L. Rabin, M.D. CBER/FDA Office of Vaccine Research and Review Laboratory of Immunobiochemistry

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Ronald L. Rabin, M.D.CBER/FDAOffice of Vaccine Research and ReviewLaboratory of Immunobiochemistry Respiratory syncytial virus (RSV): an environmental factor in the pathogenesis of asthma and allergy

  2. Asthma: a classic example of interaction between genetics and environment • Many genes linked to asthma and/or atopy are integral to innate or adaptive immunity. • Innate: CD14, TNF, TLR4, C5 • Adaptive: IL4, IL13 • Childhood exposure to house dust endotoxin (HDE) inversely correlates with asthma prevalence. • CD14 -260C/T SNP and risk for atopy: • Low HDE: decreased risk • High HDE: increased risk

  3. RSV: a viral “environmental factor?” • RSV is frequently the first pathogen infants encounter. • T cells in infants are biased towards type 2 (Th2) responses. • Type 2 T cell responses are necessary for asthma. • While we tend to focus on wheezing, asthmatics always (and sometimes only) cough. • Cough likely enhances spread of a respiratory pathogen compared to the symptoms of an uncomplicated upper respiratory infection (URI). • RSV URIs trigger bronchospasm with cough and wheezing in asthmatic children. • Asthma enhances RSV spread and survival.

  4. Epidemiologic studies correlating RSV infection with asthma--TCRS Tuscon Children’s Respiratory Study (TCRS) • Prospective longitudinal study of 1246 infants. • Differences in airway structure and multiple genetic factors may determine the development of asthma and allergy later in life (Martinez et al, N Engl J Med,1995). • RSV lower respiratory infection (LRI) increases risk for episodic wheezing associated with viral URI, but not with “true” asthma or atopy (Stein et al. Lancet, 1999). Boras, Sweden • 47 Swedish infants (30-307 days) hospitalized with RSV bronchiolitis compared with age and sex matched controls • Children evaluated for asthma and atopy at about 1 and 3 years of age. • Higher incidence of asthma in RSV group that were also skin prick test positive (SPT+)

  5. Genetic links common to asthma and severe RSV LRI

  6. Goals of project • Define the mechanisms by which RSV manipulates innate and adaptive immune responses—ultimately in the context of genotype. • Define responses to live RSV by human T cells in vitro; must determine the cause of the T cell suppression that RSV is known to induce. • Develop a simple and reproducible experimental model, limited to monocyte-derived dendritic cells (MDDC) and CD4 T cells.

  7. Live RSV is necessary for immunosuppression 15 donors Chi et al. J Virol 80:5032; 2006

  8. Suppression transfers with MDDC supernatant P < 0.01 P = 0.05 1 2 0 1 0 0 8 0 cpm (x 103) 6 0 4 0 2 0 RSV UV RSV Mock 15 donors Chi et al. J Virol 80:5032; 2006

  9. Live RSV stimulates MDDC to secrete IFN- P<0.0001 P<0.0001 4 5 0 4 0 0 3 5 0 2 0 0 1 5 0 5 0 4 0 IFN- (pg/ml) 3 0 2 0 1 0 0 RSV UVRSV Mock 15 donors Chi et al. J Virol 80:5032; 2006

  10. RSV infection induces IFN-1 gene expression by MDDC (qRT-PCR) P < 0.0001 P < 0.0001 P ｲ 0 . 0 0 0 1 24 16 4 IFN- mRNA (Ratio to -actin) 3 2 1 0 RSV UVRSV Mock 16 donors Chi et al. J Virol 80:5032; 2006

  11. IFN-a and IFN-l receptor blockade reverses RSV-induced suppression 40 30 Inhibition of CD4 T cell Proliferation (%) 20 10 0 anti-IFNAR2 - + - - + + anti-IL10R2 - - + - + - anti-IL28R - - - + - + MDDC supernatants Chi et al. J Virol 80:5032; 2006

  12. Summary/Future directions Summary: • CD4+ T cells, DC, and live RSV are sufficient to demonstrate RSV-induced immunosuppression. • Inhibition transfers with supernatant from RSV-infected DC. • IFN-a and IFN-l are expressed by MDDC in response to live RSV, and neutralizing their receptors substantially reverses RSV-induced suppression of T cells. Future directions: • Determine patterns of cytokine expression in response to RSV that are revealed by neutralizing the IFN-a and IFN-l receptors. • Compare the MDDC-mediated responses to primary myeloid and plasmacytoid DC from blood and tissue (tonsils). • Compare responses to RSV with those to other respiratory viruses (flu, RV, PIV3).

More Related