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Notch ligand-expressing adenovirus infection enhances the efficacy of dendritic cell-based immunotherapy for allergic asthma in mice

Cellular & Molecular Immunology volume 16, pages 730–732 (2019)Cite this article

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According to the World Health Organization, the prevalence of asthma is rising worldwide, and asthma causes 250,000 deaths annually.1 Allergic asthma is a type of chronic airway inflammation caused by dysregulated T helper type 2 (Th2)-type immune responses. Patients with allergic asthma are characterized by elevated serum immunoglobulin E (IgE) antibody levels, mucus production, and pulmonary inflammation as well as airway hyperresponsiveness (AHR).2 Current therapeutic methods for asthma include inhaled corticosteroids and β2 agonists to relieve asthma syndromes, but these treatments do not change the chronic disease course in patients. Some patients need high doses of inhaled corticosteroids or require long-term daily treatment with oral steroids.3 Therefore, efforts should be targeted towards developing innovative therapeutic strategies to improve patient quality of life and reduce unwanted deaths. One of the advances in the development of future therapies is the use of genetically modified dendritic cells (DCs) to decrease pathological Th2-mediated responses and maintain a disease-modifying effect long term. DC activation is crucial for inducing T cell immunity as well as determining T cell differentiation.4 Importantly, DCs can be cultured in vitro, and large amounts of generated clinical-grade DCs have become available. Additionally, DCs has been shown to be permissive of adenoviral (Ad) vector infection in vitro, and Ad vectors are a promising gene delivery platform for a variety of therapeutic and vaccine applications.5 In this regard, overexpressing immunoregulatory proteins in Ad-modified DCs would be an effective way to suppress Th2 cell immunity and establish an antiallergic response.

The Notch signaling network is a highly conserved signaling system that is an important regulator of T cell development and differentiation. In mammals, there are five Notch ligands (Delta-like 1 (DLL1), DLL3, DLL4, Jagged1, and Jagged2) and four Notch receptors (Notch1–4). The Notch pathway can be activated by Notch receptor-ligand interactions between DCs and T cells. Several studies have revealed that DLL ligands are closely associated with the development of Th1 cells, while Jagged ligands favor the induction of Th2 and regulatory T (Treg) cells. Notably, recent studies have addressed the possibility of targeting Notch in T cells to treat diseases such as autoimmune diseases, cancer, and graft transplantation. Targeting DLL1 and DLL4 via blocking antibodies ameliorates the severity of experimental autoimmune encephalomyelitis, a disease caused by an autoreactive Th1 response.6 Another study showed that Notch signaling in lymphoid cells mediated by DLL1 enhances antitumor T cell responses.7 Moreover, Lin et al. reported that the overexpression of Jagged1 prolongs allograft survival via the induction of Treg cells.6 Thus, based on this evidence, we propose that Notch may suppress excessive Th2 responses arising in an allergic state by regulating the balance of Th1/Th2 responses or inducing Treg cells. In this study, we evaluated whether bone marrow-derived DCs (BMDCs) genetically engineered to overexpress DLL4 (DLL4-DCs) can exert the therapeutic effect of inhibiting aberrant Th2-mediated allergic asthma by altering the Th1/Th2 cell ratio.

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  1. These authors contributed equally: Chu-Lun Lin, Chen-Chen Lee

Authors and Affiliations

  1. Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan, China

    Chu-Lun Lin & Yueh-Lun Lee

  2. Department of Microbiology and Immunology, School of Medicine, China Medical University, Taichung, 40402, Taiwan, China

    Chen-Chen Lee

  3. Department of Molecular Parasitology and Tropical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan, China

    Chia-Kwung Fan

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  1. Chu-Lun Lin
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Correspondence to Yueh-Lun Lee.

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Lin, CL., Lee, CC., Fan, CK. et al. Notch ligand-expressing adenovirus infection enhances the efficacy of dendritic cell-based immunotherapy for allergic asthma in mice. Cell Mol Immunol 16, 730–732 (2019). https://doi.org/10.1038/s41423-019-0250-0

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