Limits...
RSV vaccine-enhanced disease is orchestrated by the combined actions of distinct CD4 T cell subsets.

Knudson CJ, Hartwig SM, Meyerholz DK, Varga SM - PLoS Pathog. (2015)

Bottom Line: We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters.In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss.Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT
There is no currently licensed vaccine for respiratory syncytial virus (RSV) despite being the leading cause of lower respiratory tract infections in children. Children previously immunized with a formalin-inactivated RSV (FI-RSV) vaccine exhibited enhanced respiratory disease following natural RSV infection. Subsequent studies in animal models have implicated roles for CD4 T cells, eosinophils and non-neutralizing antibodies in mediating enhanced respiratory disease. However, the underlying immunological mechanisms responsible for the enhanced respiratory disease and other disease manifestations associated with FI-RSV vaccine-enhanced disease remain unclear. We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters. A Th2-biased immune response, but not eosinophils specifically, was required for airway hyperreactivity and mucus hypersecretion. In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss. Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells.

No MeSH data available.


Related in: MedlinePlus

TNF-α contributes to airway obstruction and weight loss during FI-RSV VED.BALB/c mice were immunized with FI-RSV and treated with either IgG or anti-TNF-α neutralization antibody prior to RSV challenge. (A) H&E and PAS staining were performed on immunized mice at day 4 following RSV challenge. Representative pictures were taken for each group at 200X magnification. (B) Stained lung sections were evaluated for PVA, mucus, and total histopathology scores. (C) Lower airway resistance and compliance were assessed in immunized mice at day 4 p.i. (D) Viral titers were quantified at day 4 p.i. between IgG and anti-TNF-α treated immunized mice. (E) Total numbers of eosinophils and CD4 T cells in the lungs of vaccinated mice receiving anti-TNF-α neutralizing antibody were enumerated on day 7 following RSV infection. (F) Total number of Th1 and Th2 cytokine producing cells in the lungs was quantified at day 7 post-infection following PMA and ionomycin stimulation. Data are represented as mean ± SEM of 2 independent experiments (n = 8 total mice). Groups were compared using one-way ANOVA, * p<0.05, ** p<0.01, *** p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4358888&req=5

ppat.1004757.g007: TNF-α contributes to airway obstruction and weight loss during FI-RSV VED.BALB/c mice were immunized with FI-RSV and treated with either IgG or anti-TNF-α neutralization antibody prior to RSV challenge. (A) H&E and PAS staining were performed on immunized mice at day 4 following RSV challenge. Representative pictures were taken for each group at 200X magnification. (B) Stained lung sections were evaluated for PVA, mucus, and total histopathology scores. (C) Lower airway resistance and compliance were assessed in immunized mice at day 4 p.i. (D) Viral titers were quantified at day 4 p.i. between IgG and anti-TNF-α treated immunized mice. (E) Total numbers of eosinophils and CD4 T cells in the lungs of vaccinated mice receiving anti-TNF-α neutralizing antibody were enumerated on day 7 following RSV infection. (F) Total number of Th1 and Th2 cytokine producing cells in the lungs was quantified at day 7 post-infection following PMA and ionomycin stimulation. Data are represented as mean ± SEM of 2 independent experiments (n = 8 total mice). Groups were compared using one-way ANOVA, * p<0.05, ** p<0.01, *** p<0.001.

Mentions: To determine if TNF-α also contributed to both AHR and mucus hypersecretion, or if distinct immunological mechanisms mediate separate disease manifestations, we evaluated both histology and airway hyperreactivity. The scores for degree of perivascular leukocytic aggregates, mucus, and total histopathology were significantly (p<0.01, 0.001, and 0.001 respectively) increased in FI-RSV-immunized mice following TNF-α neutralization as compared to FI-mock-immunized controls (Fig. 7A and B). However, histopathology was similar in FI-RSV-immunized mice following either IgG or anti-TNF-α treatment (Fig. 7A and B). Furthermore, neutralization of TNF-α did not significantly alter either lower airway resistance or compliance following methacholine administration (Fig. 7C).


RSV vaccine-enhanced disease is orchestrated by the combined actions of distinct CD4 T cell subsets.

Knudson CJ, Hartwig SM, Meyerholz DK, Varga SM - PLoS Pathog. (2015)

TNF-α contributes to airway obstruction and weight loss during FI-RSV VED.BALB/c mice were immunized with FI-RSV and treated with either IgG or anti-TNF-α neutralization antibody prior to RSV challenge. (A) H&E and PAS staining were performed on immunized mice at day 4 following RSV challenge. Representative pictures were taken for each group at 200X magnification. (B) Stained lung sections were evaluated for PVA, mucus, and total histopathology scores. (C) Lower airway resistance and compliance were assessed in immunized mice at day 4 p.i. (D) Viral titers were quantified at day 4 p.i. between IgG and anti-TNF-α treated immunized mice. (E) Total numbers of eosinophils and CD4 T cells in the lungs of vaccinated mice receiving anti-TNF-α neutralizing antibody were enumerated on day 7 following RSV infection. (F) Total number of Th1 and Th2 cytokine producing cells in the lungs was quantified at day 7 post-infection following PMA and ionomycin stimulation. Data are represented as mean ± SEM of 2 independent experiments (n = 8 total mice). Groups were compared using one-way ANOVA, * p<0.05, ** p<0.01, *** p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358888&req=5

ppat.1004757.g007: TNF-α contributes to airway obstruction and weight loss during FI-RSV VED.BALB/c mice were immunized with FI-RSV and treated with either IgG or anti-TNF-α neutralization antibody prior to RSV challenge. (A) H&E and PAS staining were performed on immunized mice at day 4 following RSV challenge. Representative pictures were taken for each group at 200X magnification. (B) Stained lung sections were evaluated for PVA, mucus, and total histopathology scores. (C) Lower airway resistance and compliance were assessed in immunized mice at day 4 p.i. (D) Viral titers were quantified at day 4 p.i. between IgG and anti-TNF-α treated immunized mice. (E) Total numbers of eosinophils and CD4 T cells in the lungs of vaccinated mice receiving anti-TNF-α neutralizing antibody were enumerated on day 7 following RSV infection. (F) Total number of Th1 and Th2 cytokine producing cells in the lungs was quantified at day 7 post-infection following PMA and ionomycin stimulation. Data are represented as mean ± SEM of 2 independent experiments (n = 8 total mice). Groups were compared using one-way ANOVA, * p<0.05, ** p<0.01, *** p<0.001.
Mentions: To determine if TNF-α also contributed to both AHR and mucus hypersecretion, or if distinct immunological mechanisms mediate separate disease manifestations, we evaluated both histology and airway hyperreactivity. The scores for degree of perivascular leukocytic aggregates, mucus, and total histopathology were significantly (p<0.01, 0.001, and 0.001 respectively) increased in FI-RSV-immunized mice following TNF-α neutralization as compared to FI-mock-immunized controls (Fig. 7A and B). However, histopathology was similar in FI-RSV-immunized mice following either IgG or anti-TNF-α treatment (Fig. 7A and B). Furthermore, neutralization of TNF-α did not significantly alter either lower airway resistance or compliance following methacholine administration (Fig. 7C).

Bottom Line: We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters.In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss.Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT
There is no currently licensed vaccine for respiratory syncytial virus (RSV) despite being the leading cause of lower respiratory tract infections in children. Children previously immunized with a formalin-inactivated RSV (FI-RSV) vaccine exhibited enhanced respiratory disease following natural RSV infection. Subsequent studies in animal models have implicated roles for CD4 T cells, eosinophils and non-neutralizing antibodies in mediating enhanced respiratory disease. However, the underlying immunological mechanisms responsible for the enhanced respiratory disease and other disease manifestations associated with FI-RSV vaccine-enhanced disease remain unclear. We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters. A Th2-biased immune response, but not eosinophils specifically, was required for airway hyperreactivity and mucus hypersecretion. In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss. Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells.

No MeSH data available.


Related in: MedlinePlus