# Presentation: 833463

## 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

**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**

## 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.**

## 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+)**

## Genetic links common to asthma and severe RSV LRI

## 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.**

## Live RSV is necessary for

**Live RSV is necessary for**
**immunosuppression**

**Chi *****et al. J Virol***** 80:5032; 2006**

**15 donors**

**Notes:**
RSV inhibit

## Suppression transfers with MDDC supernatant

**15 donors**

**Chi *****et al. J Virol***** 80:5032; 2006**

## Live RSV stimulates MDDC to secrete IFN-

**15 donors**

**Chi *****et al. J Virol***** 80:5032; 2006**

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**IFN-******** (pg/ml)**

**  ****RSV     UVRSV  Mock**

**P**_**<**_**0.0001**

**P**_**<**_**0.0001**

**Notes:**
There is no IFN- in the supernatant.

## RSV infection induces IFN-1 gene expression by MDDC (qRT-PCR)

**RSV infection induces IFN-********1 gene expression by MDDC (qRT-PCR)**

**16 donors**

**Chi *****et al. J Virol***** 80:5032; 2006**

## IFN- and IFN- receptor blockade reverses RSV-induced suppression

**MDDC supernatants**

**IFN-******** and IFN-******** receptor blockade reverses RSV-induced suppression**

**Chi *****et al. J Virol***** 80:5032; 2006**

## 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-******** and IFN-******** 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-******** and IFN-******** 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).**