Perinatal Immunization With Vaccine-GradeListeria monocytogenesProvides Protection Against Murine Th2 Airway Inflammation

Abstract

PurposeAsthma is a chronic respiratory disorder that leads to inflammation and narrowing of the airways. Its global prevalence has attained epidemic levels and treatment options that reach beyond temporary relief of symptoms are urgently needed. Since the processes leading to clinically symptomatic asthma start early in life, we set out to systematically evaluate a neonatal immunotherapeutic based on Listeria monocytogenes (Lm) for the control of allergic sensitization.MethodsWe modified Lm to express the model allergen, ovalbumin (OVA), and tested the ability of neonatal immunization with this strain to control allergic sensitization in a mouse model of OVA-induced asthma. Mice were immunized as newborns with live or heat killed LmOVA or live Lm, followed 6 weeks later by allergic sensitization with OVA. In order to determine whether the TH1-polarizing effect of this vaccine vector inadvertently may exacerbate development of certain TH1-driven allergic diseases, mice immunized as newborns were assessed in a model of adult hypersensitivity pneumonitis (HP).ResultsBoth LmOVA and Lm-control vaccines were highly effective in providing long-lasting protection from airway inflammation after only one immunization given perinatally. Serum antibody levels and lung cytokine production suggest that this prophylactic strategy is associated with an allergen specific TH1-dominated response. Specifically, LmOVA vaccinated mice displayed significantly elevated OVA-specific serum IgG2a, but no difference in anti-OVA IgE antibodies and only slightly decreased anti-OVA IgG1 antibodies. Importantly, Lm-based neonatal vaccination did not exacerbate Th1/Th17 driven HP, arguing against broad spectrum immune skewing.ConclusionsOur findings highlight the promise of early life Lm-based immunomodulatory interventions as a prophylactic strategy for allergic asthma.

Pneumococcal pneumonia suppresses allergy development but preserves respiratory tolerance in mice

“…three days after a first intranasal challenge period. The majority of allergy-defining parameters such as BALF eosinophilia, OVA-specific serum IgE and Th2 cytokines still demonstrated a decreased allergic phenotype, which was also true for our OVA/Spn 14 mice, whereas Th1-associated parameter IgG 2a was significantly increased which is in line with other reports supporting the effectiveness of a Th1 skewing immunomodulatory approach to suppress Th2-mediated allergic airway inflammation [28,29]. However, not only the intrinsic ability of S. pneumoniae to induce Treg production [12,30], but also a toll-like receptormediated release of IL-23 via the recruitment of neutrophils [25] might explain the reduced allergic phenotype.…”