Impaired Lung Dendritic Cell Migration and T Cell Stimulation Induced by Immunostimulatory Oligonucleotides Contribute to Reduced Allergic Airway Inflammation

Abstract

CpG-containing oligonucleotides (CpG) have been shown to reduce key features of allergic airway inflammation in mouse models. Given the inhibitory effects of CpG treatment on Ag presentation of subsequently encountered Ags via MHC class I and II molecules by dendritic cells (DC), we hypothesized that intranasal CpG treatment would lead to reduced Ag-specific T cell stimulation in the lung-draining lymph nodes, thereby reducing the inflammatory response in sensitized mice. Intranasal CpG administration led to phenotypic maturation of lung and mediastinal lymph node DC as determined by expression of MHC class II, CD80, and CD86. This was accompanied by a significant reduction in the proliferation of adoptively transferred Ag-specific CD4+ and CD8+ T cells in mediastinal lymph nodes, when CpG was given before inhalative OVA challenges. DC obtained from mediastinal lymph nodes of CpG-treated mice before OVA inhalation led to reduced T cell stimulation via MHC class I and II molecules. In addition, CpG diminished airway eosinophilia and pulmonary infiltration after sensitization or following adoptive transfer of Ag-specific Th2 cells. These results were explained by reduced CCL21 expression and inhibition of lung DC migration following CpG administration, which could be restored by transfer of bone marrow-derived DC, because CpG had no major impact on the constitutive MHC class II Ag presentation of protein-derived Ag by lung tissue-derived DC. We conclude that CpG treatment can effectively impair the DC-mediated Ag transport from the lungs to the lymph nodes, resulting in reduced T cell activation and blunted airway inflammation.

Mechanism of Action of Inhibition of Allergic Immune Responses by a Novel Antedrug TLR7 Agonist

“…In animal models, triggering of TLR9 using CpGs has been shown to be effective against many features of allergic airway inflammatory responses (43)(44)(45)(46)(47)(48)(49)(50)(51). In recent mechanistic studies, this has been shown to be dependent on production of Th1 cytokines such as IFN-g and IL-12 (43), induction of regulatory factors including upregulation of IDO (47,48), and generation of Tregs (49), as well as functional impairment of APCs (50) and inhibition of DC migration (51).…”

“…In recent mechanistic studies, this has been shown to be dependent on production of Th1 cytokines such as IFN-g and IL-12 (43), induction of regulatory factors including upregulation of IDO (47,48), and generation of Tregs (49), as well as functional impairment of APCs (50) and inhibition of DC migration (51). In terms of the dependency on Th1 cytokine generation, it is still unresolved as to whether IFN-g or IL-12 is required for prevention of Th2 immune responses with CpG treatment (46).…”

Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes

“…Additionally, the ligand for TLR9 (CpG) is being investigated in animal models and some human studies as an adjuvant for immunotherapy of allergic diseases including allergic rhinitis and asthma[3,41-43]. Although the exact mechanism of benefit is unknown, the inhibition of T H 2 cytokines may be achieved through induction of T H 1-type cytokines such as IL12, IFNα, IFNγ, or through other mechanisms[44,45] including induction of IL-10 or indoleamine 2,3-dioxygenase activity and Treg cells[46,47]. The biologic effects of TLR9 activation on allergic inflammation are likely highly complex and merit further investigation.…”

Treatment of allergic asthma: Modulation of Th2 cells and their responses

“…Such bacterial and synthetic DNA immunostimulatory oligonucleotides (ISS-ODNs) containing CpG motifs suppress Th2 responses during the sensitisation phase or immediately before challenge in experimental asthma [reviewed in [139]]. They have therapeutic and prophylactic properties [140], including suppression of DC migration and co-stimulatory molecule expression and inhibition of IgE-dependent Th2 cytokine release from mast cells and basophils [141,142]. Moreover, ISS-ODNs added to allergen immunotherapy significantly reduce clinical symptoms in patients with asthma [143].…”