Asthma is a chronic inflammatory disease affecting both children and adults. Recent studies have implicated group 2 innate lymphoid cells (ILC2s) in asthma development and exacerbation, breaking preconceived notions that T cells are the primary contributors of asthma. Importantly, ILC2s are associated with fungal allergen-associated severe asthma and corticosteroid resistant asthma in both children and adults. As such, they serve as an important therapeutic target for asthma treatment. A team led by Dr. Ya-Jen Chang discovered that ILC2-induced airway hyperreactivity (AHR) and lung inflammation could be suppressed by TLR9 immunostimulatory CpG motifs. They also demonstrate the therapeutic utility of a microparticle-based approach to locally deliver TLR9 ligands to the lungs. This study was published in the Journal of Allergy and Clinical Immunology on March 23rd, 2019.
TLR9 activation by CpG motifs have previously been shown to suppress T cell-mediated asthma through allergen-dependent mechanisms involving TH1 cells and regulatory T cells. In this study, Dr. Chang’s team identified an allergen independent, innate-driven mechanism for the suppression of ILC2-driven acute airway inflammation. By using synthetic CpG, they found that local administration of TLR9 ligand stimulates plasmacytoid dendritic cells to secrete IFN-α, which in turn activates NK cells to produce IFN-γ. IFN-γ directly inhibits ILC2 proliferation and type 2 cytokine production through STAT1-dependent mechanism. Considering that ILC2s are associated with severe and corticosteroid-resistant asthma in both children and adults, this finding underscores the therapeutic potential of using TLR9 ligands as a non-steroid alternative to manage poorly controlled asthma involving ILC2s.
Recently, immune-modifying treatments that mimic infection with natural pathogens have attracted much attention from researchers due to their therapeutic potential. In a proof-of-concept study, the team also demonstrate the feasibility and efficacy of administering non-immunogenic microparticle containing TLR9 ligand (MIS416) through local intranasal route, which is a less invasive way to deliver drugs to the lungs. Derived from commensal gram positive Propionibacterium acnes, this microparticle formulation was found to recapitulate the effects of synthetic CpG but with greater efficacy. This approach may offer an advantage over currently prescribed corticosteroids, since; by comparison, it acts upstream of inflammatory cell signaling rather than directly on pathway signaling intermediates. Moreover, this microparticle is biodegradable, and has been proven to be safe and well-tolerated by humans.
Dr. Ya-Jen Chang is an Assistant Research Fellow at the Institute of Biomedical Sciences (IBMS) in Academia Sinica. The first author, Dr. Christina Li-Ping Thio is a Postdoctoral Researcher at the IBMS. The authors collaborated with Dr. Gill Webster from Innate Immunotherapeutics (New Zealand), with their research being funded by both the Taiwan Ministry of Science and Technology (MOST) and Academia Sinica.
The article entitled “TLR9-dependent interferon production prevents group 2 innate lymphoid cell-driven airway hyperreactivity” can be found at the JACI website at: https://doi.org/10.1016/j.jaci.2019.03.008