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Mesenchymal stromal cells (MSCs) have long been considered a potential tool for treatment of allergic inflammatory diseases, owing to their immunomodulatory characteristics. In recent decades, the medical utility of MSCs has been evaluated both in vitro and in vivo, providing a foundation for therapeutic applications. However, the existing limitations of MSC therapy indicate the necessity for novel therapies. Notably, small extracellular vesicles (sEV) derived from MSCs have emerged rapidly as candidates instead of their parental cells. The acquisition of abundant and scalable MSC‐sEV is an obstacle for clinical applications. The potential application of MSC‐sEV in allergic diseases has attracted increasing attention from researchers. By carrying biological microRNAs or active proteins, MSC‐sEV can modulate the function of various innate and adaptive immune cells. In this review, we summarise the recent advances in the immunomodulatory properties of MSCs in allergic diseases, the cellular sources of MSC‐sEV, and the methods for obtaining high‐quality human MSC‐sEV. In addition, we discuss the immunoregulatory capacity of MSCs and MSC‐sEV for the treatment of asthma, atopic dermatitis, and allergic rhinitis, with a special emphasis on their immunoregulatory effects and the underlying mechanisms of immune cell modulation. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) are well known for their immunoregulatory roles on allergic inflammation particularly by acting on T cells, B cells, and dendritic cells (DCs). MSC‐derived small extracellular vesicles (MSC‐sEV) are increasingly considered as one of the main factors for the effects of MSCs on immune responses. However, the effects of MSC‐sEV on DCs in allergic diseases remain unclear. MSC‐sEV were prepared from the induced pluripotent stem cells (iPSC)‐MSCs by anion‐exchange chromatography, and were characterized with the size, morphology, and specific markers. Human monocyte‐derived DCs were generated and cultured in the presence of MSC‐sEV to differentiate the so‐called sEV‐immature DCs (sEV‐iDCs) and sEV‐mature DCs (sEV‐mDCs), respectively. The phenotypes and the phagocytic ability of sEV‐iDCs were analyzed by flow cytometry. sEV‐mDCs were co‐cultured with isolated CD4+T cells or peripheral blood mononuclear cells (PBMCs) from patients with allergic rhinitis. The levels of Th1 and Th2 cytokines produced by T cells were examined by ELISA and intracellular flow staining. And the following mechanisms were further investigated. We demonstrated that MSC‐sEV inhibited the differentiation of human monocytes to iDCs with downregulation of the expression of CD40, CD80, CD86, and HLA‐DR, but had no effects on mDCs with these markers. However, MSC‐sEV treatment enhanced the phagocytic ability of mDCs. More importantly, using anti‐IL‐10 monoclonal antibody or IL‐10Rα blocking antibody, we identified that sEV‐mDCs suppressed the Th2 immune response by reducing the production of IL‐4, IL‐9, and IL‐13 via IL‐10. Furthermore, sEV‐mDCs increased the level of Treg cells. Our study identified that mDCs treated with MSC‐sEV inhibited the Th2 responses, providing novel evidence of the potential cell‐free therapy acting on DCs in allergic airway diseases. [ABSTRACT FROM AUTHOR]

• Female mice with ILC2-dominant allergic airway inflammation exhibited higher levels of ILC2 levels compared to male mice. • The treatment of testosterone significantly decreased the intracellular type 2 cytokines ILC2. • Testosterone suppressed the proliferation of ILC2s. There were gender differences in the prevalence and severity of allergic diseases. Group 2 innate lymphoid cells (ILC2s) were recently reported to play a critical role in allergic diseases. We investigated the sex-dependent differences in ILC2-dominant allergic airway inflammation model using T\B cell-deficient mice, and determined the gender differences of ILC2 levels in patients with asthma and allergic rhinitis. Female mice exhibited higher levels of inflammatory infiltration and large production of IL-5 and IL-13, especially for ILC2 levels compared to male mice with the induction of IL-33. However, no significant differences were found for the levels of circulating ILC2s between the genders of patients. The treatment of testosterone significantly decreased the intracellular type 2 cytokines in ILC2s and the proliferation of pure ILC2s in response to epithelial cytokines. Our study suggested the sex differences and the involvement of androgen on ILC2s in allergic diseases. [ABSTRACT FROM AUTHOR]

Group 2 innate lymphoid cells (ILC2s) are recently reported to play a more critical role in allergic diseases. We previously identified that mesenchymal stromal cells (MSCs) elicited therapeutic effects on allergic airway inflammation. Small extracellular vesicles (sEV) derived from MSCs possess striking advantages including low immunogenicity and high biosafety, and is extremely promising cell-free therapeutic agents. However, the effects of MSC-sEV on ILC2s are still unclear. Additionally, scalable isolation protocols are required for the mass production of homogenous MSC-sEV especially in clinical application. We previously reported that induced pluripotent stem cells-derived MSCs were the ideal cellular source for the large preparation of MSC-sEV. Here we developed a standardized scalable protocol of anion-exchange chromatography for isolation of MSC-sEV, and investigated the effects of MSC-sEV on ILC2 function from patients with allergic rhinitis and in a mouse ILC2-dominant asthma model. The characterization of MSC-sEV was successfully demonstrated in terms of size, morphology and specific markers. Using flow cytometry and human Cytokine Antibody Array, MSC-sEV but not fibroblasts-sEV (Fb-sEV) were found to significantly inhibit the function of human ILC2s. Similarly, systemic administration of MSC-sEV but not Fb-sEV exhibited an inhibition of ILC2 levels, inflammatory cell infiltration and mucus production in the lung, a reduction in levels of T helper 2 cytokines, and alleviation of airway hyperresponsiveness in a mouse model of asthma. Using RNA sequencing, miR-146a-5p was selected as the candidate to mediate the above effects of MSC-sEV. We next revealed the uptake of ILC2s to MSC-sEV, and that transfer of miR-146a-5p in MSC-sEV to ILC2s in part contributed to the effects of MSC-sEV on ILC2s in vitro and in a mouse model. In conclusion, we demonstrated that MSC-sEV were able to prevent ILC2-dominant allergic airway inflammation at least partially through miR-146a-5p, suggesting that MSC-sEV could be a novel cell-free strategy for the treatment of allergic diseases. [ABSTRACT FROM AUTHOR]

Group 2 innate lymphoid cells (ILC2s) were reported to serve a critical role in allergic diseases. Myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) play significant roles in allergic immune response. However, effects of DCs on ILC2s in allergic diseases, especially for patients with allergic rhinitis (AR), remain unclear. We sought to address the roles of mDCs and pDCs in regulating ILC2 function in AR. mDCs and pDCs were cocultured with human PBMCs isolated from patients with AR or ILC2s to measure soluble or intracellular T H 2 cytokines, transcription factors, signaling pathways in ILC2s, and the following mechanisms were further investigated. The levels of peripheral IL-33+mDCs, pDCs, and ILC2s were studied in patients under an inhaled allergen challenge. We confirmed the presence of ILC2s, mDCs, and pDCs in the nasal mucosa of patients with AR. Both allogenic and autologous mDCs were found to activate ILC2s from patients with AR to produce T H 2 cytokines, and increase the levels of GATA-3 and signal transducer and activator of transcription signaling pathways, in which IL-33–producing mDCs exerted the major role by binding on ST2 on ILC2s. We further identified high levels of IL-33+mDCs and ILC2s in patients with AR under antigen challenge. Activated pDCs inhibited the cytokine production of ILC2s isolated from patients with AR by secretion of IL-6. mDCs promote ILC2 function by the IL-33/ST2 pathway, and activation of pDCs suppresses ILC2 function through IL-6 in patients with AR. Our findings provide new understanding of the interplay between DCs and ILC2s in allergic diseases. [ABSTRACT FROM AUTHOR]

• ST2 was highly expressed on mDCs and pDCs from patients with AR. • Allergen inhalation to patients with AR could upregulate the ST2 expression, as well as type 2 immune-related genes. • ST2+mDCs might have the potential to elicit allergic inflammation in response to IL-33. The diversity of immune responses in allergic diseases is critically mediated by dendritic cells (DCs), including myeloid and plasmacytoid DCs. Allergen inhalation increased the release of IL-33 from patients with allergic rhinitis (AR), which affecting the downstream cells by binding to its receptor (ST2). However, the effects of inhaled allergens on the expression of ST2 by DCs and IL-33 on the function of mDCs are unknown. The levels of ST2+mDCs and ST2+pDCs in the blood from patients with AR and healthy subjects were examined using flow cytometry. Moreover, the patients were challenged using the allergens and the levels of ST2+mDCs and ST2+pDCs were investigated at different time points. We found that there were higher levels of ST2+ mDCs and ST2+ pDCs in patients with AR, and these levels were further increased 0.5 h after allergen inhalation. Additionally, the type 2 immune response was upregulated after challenge. IL-33 treatment increased the expression of ST2 on mDCs. Our study demonstrated that ST2 was upregulated on DCs after allergen inhalation and that mDCs responded directly to IL-33 through ST2, suggesting that the IL-33/ST2 axis might play an important role in the pathogenesis of allergic rhinitis by DCs. [ABSTRACT FROM AUTHOR]