Induction and Inhibition of the Th2 Phenotype Spread: Implications for Childhood Asthma

Abstract

The interactions between genetic and environmental factors play a major role in the development of childhood asthma. We hypothesized that a pre-existing Th2/asthmatic response can promote Th2 responses to newly encountered Ags (i.e., phenotype spread). To test this hypothesis, we developed a mouse model in which the requirements for the induction and inhibition of phenotype spread to a clinically relevant neo-allergen (i.e., ragweed) were investigated. Our results indicate that 1) phenotype spread to the neo-allergen can be induced only within the first 8 h after a bronchial challenge with the first Ag (OVA); 2) Th2 differentiation of naive CD4+ T cells occurs in bronchial lymph nodes; 3) trafficking of naive CD4+ T cells to local lymph nodes and IL-4 produced by OVA-activated Th2 cells play essential roles in the differentiation of naive CD4+ T cells to Th2 cells; and 4) suppression of the production of chemokines involved in the homing of naive CD4+ T and Th2 cells to bronchial lymph nodes by a TLR9 agonist inhibited phenotype spread and abrogated the consequent development of experimental asthma. These findings provide a mechanistic insight into Th2 phenotype spread and offer an animal model for testing relevant immunomodulatory interventions.

Sensitization to Inhaled Ryegrass Pollen by Collateral Priming in a Murine Model of Allergic Respiratory Disease

“…Some other studies also achieved sensitization to co-administered antigens after only 1 or 2 challenges. They differ from our study by the fact that the antigens were given intranasally and in high amounts [20,21,26]. In the one study most comparable to ours [21], 100 µg of ragweed protein was given intranasally to OVA-primed mice, together with 20 µg of OVA, in order to induce Th2 spread to the ragweed proteins.…”

“…Although the first report on the possibility to expand an immune response to an antigen through the presence of another antigen in the same microenvironment dates back to 1993 [19], most data on the possible mechanisms that underlie this phenomenon are recent. It has been shown in a mouse model that Th2-type sensitization to one antigen can be transferred by inhalation to another antigen at the condition that both are given simultaneously during challenges [20,21]. This mechanism of sensitization, called collateral priming, was found to be different from the mechanisms that underlie a primary sensitization [20].…”

“…This mechanism of sensitization, called collateral priming, was found to be different from the mechanisms that underlie a primary sensitization [20]. Furthermore, it is the IL-4 produced by the already primed T cells that influences the Th2 polarization of the naïve T cells encountering a new antigen [20,21,22]. The phenomenon is thought to occur when two T cells with different specificities become activated in the same microenvironment, which might imply encounter with the same antigen-presenting dendritic cell [21].…”

“…Furthermore, it is the IL-4 produced by the already primed T cells that influences the Th2 polarization of the naïve T cells encountering a new antigen [20,21,22]. The phenomenon is thought to occur when two T cells with different specificities become activated in the same microenvironment, which might imply encounter with the same antigen-presenting dendritic cell [21]. In the present work, we intended to develop a mouse model of allergic asthma in which priming occurs after repeated aerosol exposure to low pollen allergen doses, as it occurs by repeated seasonal low-dose pollen exposure in allergic patients, and we explored whether the principle of collateral priming could induce such an airway sensitization.…”

CpG Oligodeoxynucleotide Prolongs Eosinophil Survival through Activation of Contaminating B Cells and Plasmacytoid Dendritic Cells in vitro

“…CpG ODNs are known to elicit Th1 immune responses via TLR9 and are currently under investigation in patients with various immunological disorders [16,17,18,19]. Quite recently, in vivo administration of antigen-conjugated CpG ODN has been reported to modify the response of nasal mucosa to allergen challenge by increasing Th1 cytokine production and decreasing Th2 cytokine production and eosinophilia in humans [20].…”