Inhibition of STAT6 during vaccination with formalin‐inactivated RSV prevents induction of Th2‐cell‐biased airway disease

Srinivasa, Bharat T.; Fixman, Elizabeth D.; Ward, Brian J.

doi:10.1002/eji.201344206

Cited by 9 publications

(10 citation statements)

References 39 publications

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“…The target cells through which STAT6‐IP mediated its inhibitory activity were poorly defined. Our subsequent studies and those of Michael et al. implicated DCs and macrophages in STAT6‐IP‐dependent inhibitory responses.…”

Section: Discussionsupporting

confidence: 90%

STAT6 inhibitory peptide reduces dendritic cell migration to the lymph nodes to control Th2 adaptive immunity in the mouse lung

et al. 2018

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Type 2 immunity in the lung is promoted through the release of innate cytokines, including TSLP, from lung structural cells. These cytokines drive Type 2 immunity in part through upregulation of OX40L on dendritic cells (DCs). DCs expressing OX40L are potent inducers of Th2 differentiation. We have shown previously that STAT6 inhibitory peptide (STAT6-IP), a cell penetrating peptide designed to inhibit the STAT6 transcription factor, reduces the induction of Th2 adaptive immunity in murine models of respiratory syncytial virus infection. Here we show that intranasal administration of STAT6-IP at the time of antigen priming with ovalbumin (OVA), in conjunction with the Nod2 agonist, MDP, reduced frequencies of CD11b + lung DCs expressing OX40L. Consistent with these reductions, fewer activated DCs were localized to the lung draining lymph nodes in STAT6-IP-treated mice. Upon OVA challenge four weeks later, mice treated with STAT6-IP at the time of OVA/MDP priming did not develop airway hyperresponsiveness (AHR) and had reduced influx of eosinophils into the airways, mucus production, and serum OVA-specific IgE levels. Our findings provide evidence that the long-lasting inhibitory effects of STAT6-IP are due in part to inhibition of DC responses that drive maladaptive Th2 adaptive immunity and allergic airways disease.Keywords: Airway hyperresponsiveness r Asthma r Dendritic cells r STAT6-IP r Type 2 adaptive immunity Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Section: Discussionsupporting

confidence: 90%

STAT6 inhibitory peptide reduces dendritic cell migration to the lymph nodes to control Th2 adaptive immunity in the mouse lung

et al. 2018

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“…Although we had shown that neonatal STAT6-IP exposure had beneficial effects in allergen-driven AHR, one of our concerns at the outset of the current experiments was that the STAT6-IP might inhibit the development of an effective immune response to RSV. Whereas we found similar viral titers in the lungs of all RSV-infected neonates, treated with peptide or not, RSV was undetectable in all adults previously exposed to RSV as neonates, similar to our findings in the FI-RSV vaccine model [23] (data not shown). Moreover, the IPR-R group also gained weight more rapidly after reinfection and produced equivalent cytokine profiles in lung homogenates and BALF, as well as intracellular staining of CD3 + T cells upon adult reinfection compared with the CPR-R and SALR-R groups.…”

Section: Discussionsupporting

confidence: 90%

“…STAT6-IP reduces Th2-biased airway inflammatory responses in OVA [21] and ragweed [22] models of allergic airways disease when given before allergen challenge. More recently, we have shown that STAT6-IP modulates pathogenic Th2 responses induced following RSV infection of mice previously exposed to the FI-RSV vaccine [23].…”

Section: Introductionmentioning

confidence: 99%

STAT6 inhibitory peptide given during RSV infection of neonatal mice reduces exacerbated airway responses upon adult reinfection

Srinivasa

Restori

Shan

et al. 2016

Journal of Leukocyte Biology

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Respiratory syncytial virus (RSV)-related hospitalization during infancy is strongly associated with the subsequent development of asthma. Early life RSV infection results in a Th2-biased immune response, which is also typical of asthma. Murine models of neonatal RSV infection have been developed to examine the possible contribution of RSV-driven Th2 responses to the development of airway hyper-responsiveness later in childhood. We have investigated the ability of a cell-penetrating STAT6 inhibitory peptide (STAT6-IP), when delivered selectively during neonatal RSV infection, to modify pathogenesis induced upon secondary RSV reinfection of adults 6 wk later. Neonatal STAT6-IP treatment inhibited the development of airway hyper-responsiveness (AHR) and significantly reduced lung eosinophilia and collagen deposition in adult mice following RSV reinfection. STAT6-IP-treated, RSV-infected neonates had reduced levels of both IL-4 and alternatively activated macrophages (AAMs) in the lungs. Our findings suggest that targeting STAT6 activity at the time of early-life RSV infection may effectively reduce the risk of subsequent asthma development.

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“…My results are in agreement with previous studies that demonstrate STAT6 and Th2-associated cytokines are mediators of pulmonary inflammation, mucus hypersecretion, and AHR in lung disease (331)(332)(333). Similarly, the inhibition of STAT6 signaling via administration of a STAT6 inhibitory peptide during FI-RSV immunization reduced lung inflammation, weight loss, and clinical illness following RSV challenge (334). The STAT6 inhibitory peptide may prove useful in application with other RSV vaccine candidates to inhibit a Th2-biased immune response.…”

Section: Evaluation Of Rsv Vaccine Candidates In a Murine Modelsupporting

confidence: 91%

The impact of robust memory T cell responses against respiratory syncytial virus

Knudson¹

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Inhibition of STAT6 during vaccination with formalin‐inactivated RSV prevents induction of Th2‐cell‐biased airway disease

Cited by 9 publications

References 39 publications

STAT6 inhibitory peptide reduces dendritic cell migration to the lymph nodes to control Th2 adaptive immunity in the mouse lung

STAT6 inhibitory peptide reduces dendritic cell migration to the lymph nodes to control Th2 adaptive immunity in the mouse lung

STAT6 inhibitory peptide given during RSV infection of neonatal mice reduces exacerbated airway responses upon adult reinfection

The impact of robust memory T cell responses against respiratory syncytial virus

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