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Interventions for prevention of respiratory syncytial virus bronchiolitis and sequelae in guinea pigs Sutton, Troy C.
Abstract
Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization and children who recover from RSV bronchiolitis often develop episodes of recurrent wheezing and "asthma"-like symptoms. Despite considerable research, the mechanisms causing both RSV bronchiolitis and its sequelae are poorly understood. Recent clinical studies suggest a T helper 2 (Th2) immune response may be involved in the pathogenesis of RSV bronchiolitis. By applying the T helper 1 (Thl)/T helper 2 (Th2) paradigm, we examined the effects of two interventions, (administration of "low" dose RSV or CpGODN) designed to shift the Thl/Th2 balance towards a Thl response, on the development of RSV bronchiolitis and post-bronchiolitis sequelae in a guinea pig model of experimental RSV infection. There were four groups of animals: a Sham-Inoculated Group, a Challenge Dose RSV Group (receiving ~10⁴ syncytial forming units (s.f.u.)), an Intervention Dose RSV (~10² s.f.u.) + Challenge Dose RSV Group, and a CpG-ODN + Challenge Dose RSV Group. We compared the four groups (n =11-12) during acute and chronic (days 7 and 60 post-challenge dose inoculation, respectively) RSV infection. Airway hyperresponsiveness (AHR) was measured using an acetylcholine challenge method in a whole body plethysmograph. Airway infiltration by T cells and eosinophils was assessed by point counting stained lung sections. Using a semi-quantitative RT-PCR method we compared lung IFN-ɣ/IL-5 mRNA ratios as an index of the Thl/Th2 balance and, using a RSV immunostaining technique, we assessed the proportion of animals in each group with RSV antigens in the lungs. Results on day 7 showed that the Challenge Dose RSV Group developed AHR, increased levels of airway T cells and eosinophils, a Th2 shift in lung IFN-ɣ/IL-5 mRNA ratio and showed 9/11 animals with RSV positive immunostaining. The Intervention Dose Group differed from the Challenge Dose Group in that it had a significantly lower proportion of animals with RSV positive immunostaining (1/11) and had an intermediate level of eosinophils compared to the Sham-Inoculated and Challenge Dose RSV Groups. The CpG-ODN Group did not develop AHR, a Th2 shift, or increased levels of eosinophils, but did develop an intermediate level of T cells. The CpG-ODN Group, like the Intervention Dose Group, had a significantly lower proportion of animals with RSV positive immunostaining (3/12) compared to the Challenge Dose RSV (positive control) Group, suggesting that both interventions prevented RSV infection and/or enhanced viral clearance. On day 60, the Challenge Dose RSV Group maintained AHR, elevated levels of airway T cells and eosinophils, and a Th2 shift observed on day 7, and 7/12 animals had RSV positive immunostaining. The Intervention Dose Group, on the other hand, did not maintain AHR and increased levels of T cells and eosinophils seen on day 7 and had a Thl/Th2 ratio that was not significantly different from the Sham-Inoculated or Challenge Dose RSV Group. The CpG-ODN Group was unaltered with respect to AHR, airway eosinophils, or a Th2 shift, but did have a decrease in airway T cells to a level similar to that seen in the Sham-Inoculated Group. In both the Intervention Dose Group and CpGODN Group no animals (0/12 and 0/11 respectively) had RSV positive immunostaining, suggesting that the interventions prevented the development of a persistent RSV infection. In conclusion, CpG-ODN immunotherapy protected against the development of RSV bronchiolitis, while the "low" dose intervention did not, and both interventions provided protection against the development of post-bronchiolitis sequelae in guinea pigs.
Item Metadata
Title |
Interventions for prevention of respiratory syncytial virus bronchiolitis and sequelae in guinea pigs
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2004
|
Description |
Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization and
children who recover from RSV bronchiolitis often develop episodes of recurrent
wheezing and "asthma"-like symptoms. Despite considerable research, the mechanisms
causing both RSV bronchiolitis and its sequelae are poorly understood. Recent clinical
studies suggest a T helper 2 (Th2) immune response may be involved in the pathogenesis
of RSV bronchiolitis. By applying the T helper 1 (Thl)/T helper 2 (Th2) paradigm, we
examined the effects of two interventions, (administration of "low" dose RSV or CpGODN)
designed to shift the Thl/Th2 balance towards a Thl response, on the development
of RSV bronchiolitis and post-bronchiolitis sequelae in a guinea pig model of
experimental RSV infection. There were four groups of animals: a Sham-Inoculated
Group, a Challenge Dose RSV Group (receiving ~10⁴ syncytial forming units (s.f.u.)), an
Intervention Dose RSV (~10² s.f.u.) + Challenge Dose RSV Group, and a CpG-ODN +
Challenge Dose RSV Group. We compared the four groups (n =11-12) during acute and
chronic (days 7 and 60 post-challenge dose inoculation, respectively) RSV infection.
Airway hyperresponsiveness (AHR) was measured using an acetylcholine challenge
method in a whole body plethysmograph. Airway infiltration by T cells and eosinophils
was assessed by point counting stained lung sections. Using a semi-quantitative RT-PCR
method we compared lung IFN-ɣ/IL-5 mRNA ratios as an index of the Thl/Th2 balance
and, using a RSV immunostaining technique, we assessed the proportion of animals in
each group with RSV antigens in the lungs. Results on day 7 showed that the Challenge
Dose RSV Group developed AHR, increased levels of airway T cells and eosinophils, a
Th2 shift in lung IFN-ɣ/IL-5 mRNA ratio and showed 9/11 animals with RSV positive
immunostaining. The Intervention Dose Group differed from the Challenge Dose Group
in that it had a significantly lower proportion of animals with RSV positive
immunostaining (1/11) and had an intermediate level of eosinophils compared to the
Sham-Inoculated and Challenge Dose RSV Groups. The CpG-ODN Group did not
develop AHR, a Th2 shift, or increased levels of eosinophils, but did develop an
intermediate level of T cells. The CpG-ODN Group, like the Intervention Dose Group,
had a significantly lower proportion of animals with RSV positive immunostaining (3/12)
compared to the Challenge Dose RSV (positive control) Group, suggesting that both
interventions prevented RSV infection and/or enhanced viral clearance.
On day 60, the Challenge Dose RSV Group maintained AHR, elevated levels of airway T
cells and eosinophils, and a Th2 shift observed on day 7, and 7/12 animals had RSV
positive immunostaining. The Intervention Dose Group, on the other hand, did not
maintain AHR and increased levels of T cells and eosinophils seen on day 7 and had a
Thl/Th2 ratio that was not significantly different from the Sham-Inoculated or Challenge
Dose RSV Group. The CpG-ODN Group was unaltered with respect to AHR, airway
eosinophils, or a Th2 shift, but did have a decrease in airway T cells to a level similar to
that seen in the Sham-Inoculated Group. In both the Intervention Dose Group and CpGODN
Group no animals (0/12 and 0/11 respectively) had RSV positive immunostaining,
suggesting that the interventions prevented the development of a persistent RSV
infection. In conclusion, CpG-ODN immunotherapy protected against the development
of RSV bronchiolitis, while the "low" dose intervention did not, and both interventions
provided protection against the development of post-bronchiolitis sequelae in guinea
pigs.
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Extent |
5702218 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-11-26
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0091713
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2004-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.