The Probable Role of Mesenchymal Stromal/Stem Cells and Their Exosomes in Improving Allergen Immunotherapy
-
Mahdieh Shadian Zarsabzevar
,
Kianush Charoghdoozi
,
Mohammad Javad Balighi
,
Yeganeh Khazaei
,
Amirali Ebrahimpour
,
Sajad Dehnavi
,
Mahvash Sadeghi
Abstract
Allergic asthma considered is a type I hypersensitivity disorder with increasing global prevalence and limited curative options. Mesenchymal stem cells (MSCs) and their exosomes have emerged as promising adjuncts in the control of allergic reactions. MSCs can regulate and shift the inflammatory responses and promote tissue remodeling in the airway tissues. Furthemore, exosomes derived from MSCs contribute to these effects by mediating intercellular communication and delivering bioactive molecules that modulate immune responses. This review discusses current evidence on the immunomodulatory potential and therapeutic benefits of MSCs and their exosomes in the context of allergen-specific immunotherapy (AIT) to enhance efficacy, induce long-lasting tolerance, and address current therapeutic limitations in allergic asthma.
1. Sadeghi M, Koushki K, Mashayekhi K, Ayati SH, Shahbaz SK, Moghadam M, et al. DC-targeted gold nanoparticles as an efficient and biocompatible carrier for modulating allergic responses in sublingual immunotherapy Int Immunopharmacol. 2020;86:106690.
2. Wesemann DR, Nagler CR. The microbiome, timing, and barrier function in the context of allergic disease. Immunity. 2016;44(4):728–38.
3. Li H, Tian Y, Xie L, Liu X, Huang Z, Su W. Mesenchymal stem cells in allergic diseases: Current status. Allergology International. 2020;69(1):35–45.
4. Asamoah F, Kakourou A, Dhami S, Lau S, Agache I, Muraro A, et al Allergen immunotherapy for allergic asthma: a systematic overview of systematic reviews. Clinical and translational allergy. 2017;7:1–12.
5. Papierniak ES, Lowenthal DT, Harman E. Novel therapies in asthma: leukotriene antagonists, biologic agents, and beyond. American journal of therapeutics. 2013;20(1):79–103.
6. Chesné J, Schmidt-Weber CB, von-Bieren JE. The use of adjuvants for enhancing allergen immunotherapy efficacy. Immunology and Allergy Clinics. 2016;36(1):125–45.
7. Cuppari C, Leonardi S, Manti S, Filippelli M, Alterio T, Spicuzza L, et al Allergen immunotherapy, routes of administration and cytokine networks: an update. Immunotherapy. 2014;6(6):775–86.
8. Sumi Y, Hamid Q. Airway remodeling in asthma. Allergology International. 2007;56(4):341–8.
9. Lung NH, Institute B, editors. Global initiative for asthma: global strategy for asthma management and prevention. NHLBI/WHO workshop report NHLBI publication; 1995.
10. Barnes PJ. New therapies for asthma: is there any progress? Trends in pharmacological sciences. 2010;31(7):335–43.
11. Singh D, Petavy F, Macdonald AJ, Lazaar AL, O'Connor BJ. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respiratory research. 2010;11:1–9.
12. Yazid S, Sinniah A, Solito E, Calder V, Flower RJ. Anti-allergic cromones inhibit histamine and eicosanoid release from activated human and murine mast cells by releasing Annexin A1. PLoS One. 2013;8(3):e58963.
13. Larché M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nature Reviews Immunology. 2006;6(10):761–71.
14. Dong L, Wang Y, Zheng T, Pu Y, Ma Y, Qi X, et al Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice. Stem Cell Research & Therapy. 2021;12:1–14.
15. Renesme L, Pierro M, Cobey KD, Mital R, Nangle K, Shorr R, et al Definition and characteristics of mesenchymal stromal cells in preclinical and clinical studies: a scoping review. Stem Cells Translational Medicine. 2022;11(1):44–54.
16. P De Miguel M, Fuentes-Julian S, Blazquez-Martinez A, Y Pascual C, A Aller M, Arias J, et al Immunosuppressive properties of mesenchymal stem cells: advances and applications. Current molecular medicine. 2012;12(5):574–91.
17. Le Blanc K, Ringden O. Immunomodulation by mesenchymal stem cells and clinical experience. Journal of internal medicine. 2007;262(5):509–25.
18. Markov A, Thangavelu L, Aravindhan S, Zekiy AO, Jarahian M, Chartrand MS, et al Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders. Stem cell research & therapy. 2021;12:1–30.
19. Genç D, Zibandeh N, Nain E, Gökalp M, Özen A, Göker M, et al Dental follicle mesenchymal stem cells down‐regulate Th2‐mediated immune response in asthmatic patients mononuclear cells. Clinical & Experimental Allergy. 2018;48(6):663–78.
20. Lin S-C, Liou Y-M, Ling T-Y, Chuang Y-H, Chiang B-L. Placenta-derived mesenchymal stem cells reduce the interleukin-5 level experimentally in children with asthma. International journal of medical sciences. 2019;16(11):1430.
21. Hofmann NA, Ortner A, Jacamo RO, Reinisch A, Schallmoser K, Rohban R, et al Oxygen sensing mesenchymal progenitors promote neo-vasculogenesis in a humanized mouse model in vivo. 2012.
22. Bell GI, Meschino MT, Hughes-Large JM, Broughton HC, Xenocostas A, Hess DA. Combinatorial human progenitor cell transplantation optimizes islet regeneration through secretion of paracrine factors. Stem cells and development. 2012;21(11):1863–76.
23. Zhao S, Wehner R, Bornhäuser M, Wassmuth R, Bachmann M, Schmitz M. Immunomodulatory properties of mesenchymal stromal cells and their therapeutic consequences for immune-mediated disorders. Stem cells and development. 2010;19(5):607–14.
24. Waszak P, Alphonse R, Vadivel A, Ionescu L, Eaton F, Thébaud B. Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. Stem cells and development. 2012;21(15):2789–97.
25. Dabrowska S, Andrzejewska A, Janowski M, Lukomska B. Immunomodulatory and regenerative effects of mesenchymal stem cells and extracellular vesicles: therapeutic outlook for inflammatory and degenerative diseases. Frontiers in immunology. 2021;11:591065.
26. Sun Y-Q, Deng M-X, He J, Zeng Q-X, Wen W, Wong DS, et al Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice. Stem cells. 2012;30(12):2692–9.
27. Abreu SC, Weiss DJ, Rocco PR. Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases? Stem cell research & therapy. 2016;7:1–10.
28. Hong GH, Kwon H-S, Lee KY, Ha EH, Moon K-A, Kim SW, et al hMSCs suppress neutrophil-dominant airway inflammation in a murine model of asthma. Experimental & molecular medicine. 2017;49(1):e288-e.
29. Trzil JE, Masseau I, Webb TL, Chang CH, Dodam JR, Cohn LA, et al Long‐term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma. Clinical & Experimental Allergy. 2014;44(12):1546–57.
30. Fu Y, Li J, Zhang Z, Ren F, Wang Y, Jia H, et al Umbilical cord mesenchymal stem cell‐derived exosomes alleviate collagen‐induced arthritis by balancing the population of Th17 and regulatory T cells. FEBS letters. 2022;596(20):2668–77.
31. Mo Y, Kang S-Y, Bang J-Y, Kim Y, Jeong J, Jeong E-M, et al Intravenous mesenchymal stem cell administration modulates monocytes/macrophages and ameliorates asthmatic airway inflammation in a murine asthma model. Molecules and cells. 2022;45(11):833–45.
32. Choi JY, Hur J, Jeon S, Jung CK, Rhee CK. Effects of human adipose tissue-and bone marrow-derived mesenchymal stem cells on airway inflammation and remodeling in a murine model of chronic asthma. Scientific Reports. 2022;12(1):12032.
33. Yao Y, Fan X-L, Jiang D, Zhang Y, Li X, Xu Z-B, et al Connexin 43-mediated mitochondrial transfer of iPSC-MSCs alleviates asthma inflammation. Stem cell reports. 2018;11(5):1120–35.
34. Royce SG, Mao W, Lim R, Kelly K, Samuel CS. iPSC‐and mesenchymoangioblast‐derived mesenchymal stem cells provide greater protection against experimental chronic allergic airways disease compared with a clinically used corticosteroid. The FASEB Journal. 2019;33(5):6402–11.
35. Fang S-B, Zhang H-Y, Jiang A-Y, Fan X-L, Lin Y-D, Li C-L, et al Human iPSC-MSCs prevent steroid-resistant neutrophilic airway inflammation via modulating Th17 phenotypes. Stem cell research & therapy. 2018;9:1–12.
36. Bentley JK, Popova AP, Bozyk PD, Linn MJ, Baek AE, Lei J, et al Ovalbumin sensitization and challenge increases the number of lung cells possessing a mesenchymal stromal cell phenotype. Respiratory Research. 2010;11:1–15.
37. Ou-Yang H-F, Huang Y, Hu X-B, Wu C-G. Suppression of allergic airway inflammation in a mouse model of asthma by exogenous mesenchymal stem cells. Experimental biology and medicine. 2011;236(12):1461–7.
38. Gao P, Zhou Y, Xian L, Li C, Xu T, Plunkett B, et al Functional effects of TGF-β1 on mesenchymal stem cell mobilization in cockroach allergen–induced asthma. The Journal of Immunology. 2014;192(10):4560–70.
39. Xu T, Zhou Y, Qiu L, Do DC, Zhao Y, Cui Z, et al Aryl hydrocarbon receptor protects lungs from cockroach allergen–induced inflammation by modulating mesenchymal stem cells. The Journal of Immunology. 2015;195(12):5539–50.
40. Yu X, Yu L, Guo B, Chen R, Qiu C. A narrative review of research advances in mesenchymal stem cell therapy for asthma. Annals of Translational Medicine. 2020;8(21).
41. Fu Q, Chow Y, Sun S, Zeng Q, Li H, Shi J, et al Mesenchymal stem cells derived from human induced pluripotent stem cells modulate T‐cell phenotypes in allergic rhinitis. Allergy. 2012;67(10):1215–22.
42. Li Y, Li H, Cao Y, Wu F, Ma W, Wang Y, et al Placenta-derived mesenchymal stem cells improve airway hyperresponsiveness and inflammation in asthmatic rats by modulating the Th17/Treg balance. Molecular medicine reports. 2017;16(6):8137–45.
43. Zeng SL, Wang LH, Li P, Wang W, Yang J. Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function. Molecular Medicine Reports. 2015;12(2):2511–20.
44. Brown JM, Nemeth K, Kushnir‐Sukhov NM, Metcalfe DD, Mezey E. Bone marrow stromal cells inhibit mast cell function via a COX2‐dependent mechanism. Clinical & Experimental Allergy. 2011;41(4):526–34.
45. Fan X, Xu Z-B, Li C-L, Zhang H-Y, Peng Y-Q, He B-X, et al Mesenchymal stem cells regulate type 2 innate lymphoid cells via regulatory T cells through ICOS-ICOSL interaction. Stem Cells. 2021;39(7):975–87.
46. Kim RL, Bang J-Y, Kim J, Mo Y, Kim Y, Lee C-G, et al Mesenchymal stem cells exert their anti-asthmatic effects through macrophage modulation in a murine chronic asthma model. Scientific Reports. 2022;12(1):9811.
47. Wang M, Zhao N, Wang C, Jin ZB, Zhang L. Immunomodulatory properties of mesenchymal stem cells: A potential therapeutic strategy for allergic rhinitis. Allergy. 2023;78(6):1425–40.
48. Ma S-Y, Zhao N, Cui L, Li Y, Zhang H, Wang J, et al Therapeutic effects of human pluripotent stem cell-derived mesenchymal stem cells on a murine model of acute Type-2-dominated airway inflammation. Stem Cell Reviews and Reports. 2022;18(8):2939–51.
49. Michaeloudes C, Li X, Mak JC, Bhavsar PK. Study of mesenchymal stem cell-mediated mitochondrial transfer in in vitro models of oxidant-mediated airway epithelial and smooth muscle cell injury. In Vitro Models for Stem Cell Therapy: Methods and Protocols. 2021:93–105.
50. Keyhanmanesh R, Rahbarghazi R, Aslani MR, Hassanpour M, Ahmadi M. Systemic delivery of mesenchymal stem cells condition media in repeated doses acts as magic bullets in restoring IFN-γ/IL-4 balance in asthmatic rats. Life sciences. 2018;212:30–6.
51. Keyhanmanesh R, Khodamoradi F, Rahbarghazi R, Rahbarghazi A, Rezaie J, Ahmadi M, et al Intra-tracheal delivery of mesenchymal stem cell-conditioned medium ameliorates pathological changes by inhibiting apoptosis in asthmatic rats. Molecular Biology Reports. 2022;49(5):3721–8.
52. Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, et al The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduction and Targeted Therapy. 2022;7(1):92.
53. Sun L, Sha J, Meng C, Zhu D. Mesenchymal stem cell‐based therapy for allergic rhinitis. Stem Cells International. 2020;2020(1):2367524.
54. Gao F, Chiu S, Motan D, Zhang Z, Chen L, Ji H, et al Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell death & disease. 2016;7(1):e2062-e.
55. Jiang W, Xu J. Immune modulation by mesenchymal stem cells. Cell proliferation. 2020;53(1):e12712.
56. Park I-S, Kim JH, Bae J-S, Kim D-K, Mo J-H. The supernatant of tonsil‐derived mesenchymal stem cell has antiallergic effects in allergic rhinitis mouse model. Mediators of Inflammation. 2020;2020(1):6982438.
57. Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature medicine. 2009;15(1):42–9.
58. Hyvärinen K, Holopainen M, Skirdenko V, Ruhanen H, Lehenkari P, Korhonen M, et al Mesenchymal stromal cells and their extracellular vesicles enhance the anti-inflammatory phenotype of regulatory macrophages by downregulating the production of interleukin (IL)-23 and IL-22. Frontiers in immunology. 2018;9:771.
59. Abumaree M, Al Jumah M, Kalionis B, Jawdat D, Al Khaldi A, Abomaray F, et al Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti-inflammatory M2 macrophages. Stem Cell Reviews and Reports. 2013;9:620–41.
60. Nemeth K, Keane-Myers A, Brown JM, Metcalfe DD, Gorham JD, Bundoc VG, et al Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma. Proceedings of the National Academy of Sciences. 2010;107(12):5652–7.
61. Zhong H, Fan X-L, Fang S-B, Lin Y-D, Wen W, Fu Q-L. Human pluripotent stem cell-derived mesenchymal stem cells prevent chronic allergic airway inflammation via TGF-β1-Smad2/Smad3 signaling pathway in mice. Molecular immunology. 2019;109:51–7.
62. Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2, 3-dioxygenase expression. Transplantation. 2010;90(12):1312–20.
63. Dai Y-Y, Ni S-Y, Ma K, Ma Y-S, Wang Z-S, Zhao X-L. Stem cells from human exfoliated deciduous teeth correct the immune imbalance of allergic rhinitis via Treg cells in vivo and in vitro. Stem Cell Research & Therapy. 2019;10:1–14.
64. Wang G, Cao K, Liu K, Xue Y, Roberts AI, Li F, et al Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells. Cell Death & Differentiation. 2018;25(7):1209–23.
65. Lee K, Ko E, Park Y. Adipose Tissue-Derived Mesenchymal Stem Cell Inhibits Osteoclast Differentiation through Tumor Necrosis Factor Stimulated Gene-6. Tissue Engineering and Regenerative Medicine. 2024;21(4):587–94.
66. Day AJ, Milner CM. TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties. Matrix Biology. 2019;78:60–83.
67. Mittal M, Tiruppathi C, Nepal S, Zhao Y-Y, Grzych D, Soni D, et al TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Proceedings of the National Academy of Sciences. 2016;113(50):E8151-E8.
68. Wortzel I, Dror S, Kenific CM, Lyden D. Exosome-Mediated Metastasis: Communication from a Distance. Dev Cell. 2019;49(3):347–60.
69. Liu P, Wang W, Wang F, Fan J, Guo J, Wu T, et al Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer. J Transl Med. 2023;21(1):40.
70. Oveili E, Vafaei S, Bazavar H, Eslami Y, Mamaghanizadeh E, Yasamineh S, et al The potential use of mesenchymal stem cells-derived exosomes as microRNAs delivery systems in different diseases. Cell Communication and Signaling. 2023;21(1):20.
71. Sun Y, Liu G, Zhang K, Cao Q, Liu T, Li J. Mesenchymal stem cells-derived exosomes for drug delivery. Stem cell research & therapy. 2021;12:1–15.
72. Cai J, Wu J, Wang J, Li Y, Hu X, Luo S, et al Extracellular vesicles derived from different sources of mesenchymal stem cells: therapeutic effects and translational potential. Cell & bioscience. 2020;10:1–14.
73. Lai RC, Yeo RWY, Tan KH, Lim SK. Exosomes for drug delivery — a novel application for the mesenchymal stem cell. Biotechnology Advances. 2013;31(5):543–51.
74. Riazifar M, Mohammadi MR, Pone EJ, Yeri A, Lasser C, Segaliny AI, et al Stem cell-derived exosomes as nanotherapeutics for autoimmune and neurodegenerative disorders. ACS nano. 2019;13(6):6670–88.
75. Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Molecular Therapy. 2015;23(5):812–23.
76. Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem cell research & therapy. 2016;7:1–13.
77. Yin K, Wang S, Zhao RC. Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomarker research. 2019;7:1–8.
78. Torregrosa Paredes P, Esser J, Admyre C, Nord M, Rahman Q, Lukic A, et al Bronchoalveolar lavage fluid exosomes contribute to cytokine and leukotriene production in allergic asthma. Allergy. 2012;67(7):911–9.
79. Masyuk AI, Masyuk TV, LaRusso NF. Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases. Journal of hepatology. 2013;59(3):621–5.
80. de Castro LL, Xisto DG, Kitoko JZ, Cruz FF, Olsen PC, Redondo PAG, et al Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma. Stem cell research & therapy. 2017;8:1–12.
81. Dong B, Wang C, Zhang J, Zhang J, Gu Y, Guo X, et al Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization. Stem Cell Research & Therapy. 2021;12:1–17.
82. Ferguson SW, Wang J, Lee CJ, Liu M, Neelamegham S, Canty JM, et al The microRNA regulatory landscape of MSC-derived exosomes: a systems view. Scientific reports. 2018;8(1):1419.
83. Xun C, Ge L, Tang F, Wang L, Zhuo Y, Long L, et al Insight into the proteomic profiling of exosomes secreted by human OM-MSCs reveals a new potential therapy. Biomedicine & Pharmacotherapy. 2020;131:110584.
84. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. science. 2020;367(6478):eaau6977.
85. Wu J, Kuang L, Chen C, Yang J, Zeng W-N, Li T, et al miR-100–5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. Biomaterials. 2019;206:87–100.
86. Zhao J, Li X, Hu J, Chen F, Qiao S, Sun X, et al Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovascular research. 2019;115(7):1205–16.
87. Cao J-Y, Wang B, Tang T-T, Wen Y, Li Z-L, Feng S-T, et al Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury. Theranostics. 2021;11(11):5248.
88. Wei H, Xu Y, Chen Q, Chen H, Zhu X, Li Y. Mesenchymal stem cell-derived exosomal miR-223 regulates neuronal cell apoptosis. Cell death & disease. 2020;11(4):290.
89. Han S, Ma C, Bao L, Lv L, Huang M. miR-146a mimics attenuate allergic airway inflammation by impacted group 2 innate lymphoid cells in an ovalbumin-induced asthma mouse model. International Archives of Allergy and Immunology. 2018;177(4):302–10.
90. Zhang X-H, Zhang Y-N, Li H-B, Hu C-Y, Wang N, Cao P-P, et al Overexpression of miR-125b, a novel regulator of innate immunity, in eosinophilic chronic rhinosinusitis with nasal polyps. American journal of respiratory and critical care medicine. 2012;185(2):140–51.
91. Bu X, Wang M, Luan G, Wang Y, Wang C, Zhang L, editors. Integrated miRNA and mRNA expression profiling reveals dysregulated miRNA‐mRNA regulatory networks in eosinophilic and non‐eosinophilic chronic rhinosinusitis with nasal polyps. International Forum of Allergy & Rhinology; 2021: Wiley Online Library.
92. Langwiński W, Szczepankiewicz D, Narożna B, Stegmayr J, Wagner D, Alsafadi H, et al Allergic inflammation in lungs and nasal epithelium of rat model is regulated by tissue-specific miRNA expression. Molecular Immunology. 2022;147:115–25.
93. Zhou Y, Zhang T, Yan Y, You B, You Y, Zhang W, et al MicroRNA-223–3p regulates allergic inflammation by targeting INPP4A. Brazilian Journal of Otorhinolaryngology. 2021;87(5):591–600.
94. Lyu B, Wei Z, Jiang L, Ma C, Yang G, Han S. MicroRNA-146a negatively regulates IL-33 in activated group 2 innate lymphoid cells by inhibiting IRAK1 and TRAF6. Genes & Immunity. 2020;21(1):37–44.
95. Li Z, Liu F, He X, Yang X, Shan F, Feng J. Exosomes derived from mesenchymal stem cells attenuate inflammation and demyelination of the central nervous system in EAE rats by regulating the polarization of microglia. International immunopharmacology. 2019;67:268–80.
96. Lopatina T, Bruno S, Tetta C, Kalinina N, Porta M, Camussi G. Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Communication and Signaling. 2014;12:1–12.
97. Yi X, Wei X, Lv H, An Y, Li L, Lu P, et al Exosomes derived from microRNA-30b-3p-overexpressing mesenchymal stem cells protect against lipopolysaccharide-induced acute lung injury by inhibiting SAA3. Experimental cell research. 2019;383(2):111454.
98. Lu F-B, Chen D-Z, Chen L, Hu E-D, Wu J-L, Li H, et al Attenuation of experimental autoimmune hepatitis in mice with bone mesenchymal stem cell-derived exosomes carrying microRNA-223–3p. Molecules and cells. 2019;42(12):906–18.
99. Du W, Zhang K, Zhang S, Wang R, Nie Y, Tao H, et al Enhanced proangiogenic potential of mesenchymal stem cell-derived exosomes stimulated by a nitric oxide releasing polymer. Biomaterials. 2017;133:70–81.
100. wei Li J, Wei L, Han Z, Chen Z. Mesenchymal stromal cells-derived exosomes alleviate ischemia/reperfusion injury in mouse lung by transporting anti-apoptotic miR-21–5p. European Journal of Pharmacology. 2019;852:68–76.
101. Gao S, Chen T, Hao Y, Zhang F, Tang X, Wang D, et al Exosomal miR-135a derived from human amnion mesenchymal stem cells promotes cutaneous wound healing in rats and fibroblast migration by directly inhibiting LATS2 expression. Stem Cell Research & Therapy. 2020;11:1–11.
102. Tao S-C, Guo S-C, Li M, Ke Q-F, Guo Y-P, Zhang C-Q. Chitosan wound dressings incorporating exosomes derived from microRNA-126-overexpressing synovium mesenchymal stem cells provide sustained release of exosomes and heal full-thickness skin defects in a diabetic rat model. Stem cells translational medicine. 2017;6(3):736–47.
103. Bunggulawa EJ, Wang W, Yin T, Wang N, Durkan C, Wang Y, et al Recent advancements in the use of exosomes as drug delivery systems. Journal of nanobiotechnology. 2018;16:1–13.
104. Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, et al Exosomes as drug delivery vehicles for Parkinson's disease therapy. Journal of controlled release. 2015;207:18–30.
105. Engeroff P, Vogel M. The Potential of Exosomes in Allergy Immunotherapy. Vaccines. 2022;10(1):133.
106. Shahir M, Mahmoud Hashemi S, Asadirad A, Varahram M, Kazempour‐Dizaji M, Folkerts G, et al Effect of mesenchymal stem cell‐derived exosomes on the induction of mouse tolerogenic dendritic cells. Journal of cellular physiology. 2020;235(10):7043–55.
107. Dehnavi S, Khodadadi A, Asadirad A, Ghadiri AA. Immune response modulation by allergen loaded into mesenchymal stem cell-derived exosomes as an effective carrier through sublingual immunotherapy. Immunobiology. 2023;228(3):152361.
108. Shahzad KA, Wang Z, Li X, Li J, Xu M, Tan F. Immunomodulatory effect of PLGA-encapsulated mesenchymal stem cells-derived exosomes for the treatment of allergic rhinitis. Frontiers in Immunology. 2024;15:1429442.
109. Fang S-B, Zhang H-Y, Meng X-C, Wang C, He B-X, Peng Y-Q, et al Small extracellular vesicles derived from human MSCs prevent allergic airway inflammation via immunomodulation on pulmonary macrophages. Cell death & disease. 2020;11(6):409.
110. Di Trapani M, Bassi G, Midolo M, Gatti A, Takam Kamga P, Cassaro A, et al Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions. Scientific reports. 2016;6(1):24120.
111. Fang S-B, Zhang H-Y, Wang C, He B-X, Liu X-Q, Meng X-C, et al Small extracellular vesicles derived from human mesenchymal stromal cells prevent group 2 innate lymphoid cell-dominant allergic airway inflammation through delivery of miR-146a-5p. Journal of extracellular vesicles. 2020;9(1):1723260.
112. Reis M, Mavin E, Nicholson L, Green K, Dickinson AM, Wang X-n. Mesenchymal stromal cell-derived extracellular vesicles attenuate dendritic cell maturation and function. Frontiers in immunology. 2018;9:2538.
113. Peng YQ, Deng XH, Xu ZB, Wu ZC, Fu QL. Mesenchymal stromal cells and their small extracellular vesicles in allergic diseases: From immunomodulation to therapy. European Journal of Immunology. 2023;53(10):2149510.
114. Zargar MJ, Kaviani S, Vasei M, Soufi Zomorrod M, Heidari Keshel S, Soleimani M. Therapeutic role of mesenchymal stem cell-derived exosomes in respiratory disease. Stem Cell Research & Therapy. 2022;13(1):194.
115. Hong D, Hu Z, Weng J, Yang L, Xiong Y, Liu Y. Effect of mesenchymal stem cell therapy in animal models of allergic rhinitis: A systematic review and meta-analysis. International Immunopharmacology. 2023;124:111003.
116. Dehnavi S, Khodadadi A, Asadirad A, Ghadiri A. Loading Ovalbumin into Mesenchymal Stem Cell-Derived Exosomes as a Nanoscale Carrier with Immunomodulatory Potential for Allergen-Specific Immunotherapy. Reports of Biochemistry & Molecular Biology. 2023;11(4):626.
117. Cruz FF, Borg ZD, Goodwin M, Sokocevic D, Wagner DE, Coffey A, et al Systemic administration of human bone marrow-derived mesenchymal stromal cell extracellular vesicles ameliorates aspergillus hyphal extract-induced allergic airway inflammation in immunocompetent mice. Stem cells translational medicine. 2015;4(11):1302–16.
118. Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organization Journal. 2015;8:1–12.
119. Wang M, Takeda K, Shiraishi Y, Okamoto M, Dakhama A, Joetham A, et al Peanut-induced intestinal allergy is mediated through a mast cell–IgE–FcεRI–IL-13 pathway. Journal of Allergy and Clinical Immunology. 2010;126(2):306–16. e12.
120. Cho K-S, Park M-K, Kang S-A, Park H-Y, Hong S-L, Park H-K, et al Adipose‐derived stem cells ameliorate allergic airway inflammation by inducing regulatory T cells in a mouse model of asthma. Mediators of Inflammation. 2014;2014(1):436476.
121. Dai R, Yu Y, Yan G, Hou X, Ni Y, Shi G. Intratracheal administration of adipose derived mesenchymal stem cells alleviates chronic asthma in a mouse model. BMC pulmonary medicine. 2018;18:1–9.
122. Kavanagh H, Mahon BP. Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells. Allergy. 2011;66(4):523–31.
123. Pai S, Muruganandah V, Kupz A. What lies beneath the airway mucosal barrier? Throwing the spotlight on antigen‐presenting cell function in the lower respiratory tract. Clinical & Translational Immunology. 2020;9(7):e1158.
124. Liu J, Zhang X, Cheng Y, Cao X. Dendritic cell migration in inflammation and immunity. Cellular & molecular immunology. 2021;18(11):2461–71.
125. Gazi U, Bahceciler NN. Immune mechanisms induced by sublingual immunotherapy in allergic respiratory diseases. Clin Exp Immunol. 2022;209(3):262–9.
126. Chiesa S, Morbelli S, Morando S, Massollo M, Marini C, Bertoni A, et al Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proceedings of the National Academy of Sciences. 2011;108(42):17384–9.
127. Mathias LJ, Khong SM, Spyroglou L, Payne NL, Siatskas C, Thorburn AN, et al Alveolar macrophages are critical for the inhibition of allergic asthma by mesenchymal stromal cells. The Journal of Immunology. 2013;191(12):5914–24.
128. Takeda K, Webb TL, Ning F, Shiraishi Y, Regan DP, Chow L, et al Mesenchymal stem cells recruit CCR2+ monocytes to suppress allergic airway inflammation. The Journal of Immunology. 2018;200(4):1261–9.
129. Wang X, Thomsen P. Mesenchymal stem cell–derived small extracellular vesicles and bone regeneration. Basic & clinical pharmacology & toxicology. 2021;128(1):18–36.
130. Lelek J, Zuba-Surma EK. Perspectives for future use of extracellular vesicles from umbilical cord-and adipose tissue-derived mesenchymal stem/stromal cells in regenerative therapies—synthetic review. International journal of molecular sciences. 2020;21(3):799.
131. Tieu A, Slobodian M, Fergusson DA, Montroy J, Burger D, Stewart DJ, et al Methods and efficacy of extracellular vesicles derived from mesenchymal stromal cells in animal models of disease: a preclinical systematic review protocol. Systematic reviews. 2019;8:1–8.
132. Du Y-m, Zhuansun Y-x, Chen R, Lin L, Lin Y, Li J-g. Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma. Experimental Cell Research. 2018;363(1):114–20.
133. Zhuansun Y, Du Y, Huang F, Lin L, Chen R, Jiang S, et al MSCs exosomal miR-1470 promotes the differentiation of CD4+ CD25+ FOXP3+ Tregs in asthmatic patients by inducing the expression of P27KIP1. International Immunopharmacology. 2019;77:105981.
134. Groß F, Metzner G, Behn U. Mathematical modeling of allergy and specific immunotherapy: Th1–Th2–Treg interactions. Journal of theoretical biology. 2011;269(1):70–8.
135. Amu S, Saunders SP, Kronenberg M, Mangan NE, Atzberger A, Fallon PG. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model. Journal of Allergy and Clinical Immunology. 2010;125(5):1114–24. e8.
136. van de Veen W. The role of regulatory B cells in allergen immunotherapy. Current opinion in allergy and clinical immunology. 2017;17(6):447–52.
137. Palomares O, Yaman G, Azkur AK, Akkoc T, Akdis M, Akdis CA. Role of Treg in immune regulation of allergic diseases. European journal of immunology. 2010;40(5):1232–40.
138. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–5.
139. Pavón-Romero GF, Parra-Vargas MI, Ramírez-Jiménez F, Melgoza-Ruiz E, Serrano-Pérez NH, Teran LM. Allergen Immunotherapy: Current and Future Trends. Cells. 2022;11(2).
140. Mirra V, Montella S, Santamaria F. Pediatric severe asthma: a case series report and perspectives on anti-IgE treatment. Bmc Pediatrics. 2018;18:1–11.
141. Senti G, Freiburghaus AU, Larenas-Linnemann D, Hoffmann HJ, Patterson AM, Klimek L, et al Intralymphatic Immunotherapy: Update and Unmet Needs. Int Arch Allergy Immunol. 2019;178(2):141–9.
142. Calderon M, Simons F, Malling HJ, Lockey R, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy. 2012;67(3):302–11.
143. Cox L. Sublingual immunotherapy and allergic rhinitis. Current Allergy and Asthma Reports. 2008;8(2):102–10.
144. Yukselen A, Kendirli SG. Role of immunotherapy in the treatment of allergic asthma. World J Clin Cases. 2014;2(12):859–65.
145. Burks AW, Calderon MA, Casale T, Cox L, Demoly P, Jutel M, et al Update on allergy immunotherapy: American academy of allergy, asthma & immunology/European academy of allergy and clinical immunology/PRACTALL consensus report. Journal of Allergy and Clinical Immunology. 2013;131(5):1288–96. e3.
146. Tsabouri S, Mavroudi A, Feketea G, Guibas GV. Subcutaneous and sublingual immunotherapy in allergic asthma in children. Frontiers in Pediatrics. 2017;5:82.
147. Calderón MA, Casale TB, Togias A, Bousquet J, Durham SR, Demoly P. Allergen-specific immunotherapy for respiratory allergies: from meta-analysis to registration and beyond. Journal of Allergy and Clinical Immunology. 2011;127(1):30–8.
148. Sadeghi M, Shahbaz SK, Dehnavi S, Koushki K, Sankian M. Current possibilities and future perspectives for improving efficacy of allergen-specific sublingual immunotherapy. International Immunopharmacology. 2021;101:108350.
149. Asadirad A, Ghadiri AA, Amari A, Ghasemi Dehcheshmeh M, Sadeghi M, Dehnavi S. Sublingual prophylactic administration of OVA-loaded MSC-derived exosomes to prevent allergic sensitization. International Immunopharmacology. 2023;120:110405.
150. Liu W, Ota M, Tabushi M, Takahashi Y, Takakura Y. Development of allergic rhinitis immunotherapy using antigen-loaded small extracellular vesicles. Journal of Controlled Release. 2022;345:433–42.
151. Firouzabadi SR, Mohammadi I, Ghafourian K, Kiani A, Hashemi SM. Mesenchymal stem cell-derived extracellular vesicle therapy for asthma in murine models: a systematic review and meta-analysis. Stem Cell Reviews and Reports. 2024;20(5):1162–83.
152. Chen S, Gao J, Zhang T. From mesenchymal stem cells to their extracellular vesicles: progress and prospects for asthma therapy. Asian Journal of Pharmaceutical Sciences. 2024;19(4):100942.
153. Wang W, Han ZC. Heterogeneity of human mesenchymal stromal/stem cells. Stem Cells Heterogeneity-Novel Concepts. 2019:165–77.
154. Moslehi D, Nahm WJ, Serwald G, Bigham Z, Nambudiri VE. Exosomes in precision dermatology: From biomarkers to targeted therapeutics in personalized care. Journal of the European Academy of Dermatology and Venereology. 2026.
155. Patel GK, Khan MA, Zubair H, Srivastava SK, Khushman Md, Singh S, et al Comparative analysis of exosome isolation methods using culture supernatant for optimum yield, purity and downstream applications. Scientific reports. 2019;9(1):5335.
156. Dai Y-Y, Ni S-Y, Ma K, Ma Y-S, Wang Z-S, Zhao X-L. Stem cells from human exfoliated deciduous teeth correct the immune imbalance of allergic rhinitis via Treg cells in vivo and in vitro. Stem Cell Research & Therapy. 2019;10(1):39.
157. Wenjin L, Yanjie W, Xueping Q, Yunfang A, Changqing Z. Research advances of mesenchymal stem cell in allergic rhinitis. Journal of Clinical Otorhinolaryngology Head and Neck Surgery. 2024;38(5):442.
158. Chattopadhyay S, Rajendran RL, Chatterjee G, Reyaz D, Prakash K, Hong CM, et al Mesenchymal stem cell-derived exosomes: a paradigm shift in clinical therapeutics. Experimental Cell Research. 2025;450(1):114616.
159. Schwarzenbach H, Gahan PB. Exosomes in immune regulation. Non-coding RNA. 2021;7(1):4.
160. Lotfy A, AboQuella NM, Wang H. Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials. Stem cell research & therapy. 2023;14(1):66.
161. Ma CY, Zhai Y, Li CT, Liu J, Xu X, Chen H, et al Translating mesenchymal stem cell and their exosome research into GMP compliant advanced therapy products: promises, problems and prospects. Medicinal research reviews. 2024;44(3):919–38.
162. Pan W, Chen H, Wang A, Wang F, Zhang X. Challenges and strategies: scalable and efficient production of mesenchymal stem cells-derived exosomes for cell-free therapy. Life sciences. 2023;319:121524.
163. Almeria C, Kreß S, Weber V, Egger D, Kasper C. Heterogeneity of mesenchymal stem cell-derived extracellular vesicles is highly impacted by the tissue/cell source and culture conditions. Cell & bioscience. 2022;12(1):51.
164. Welsh JA, Goberdhan DC, O'Driscoll L, Buzas EI, Blenkiron C, Bussolati B, et al Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. Journal of extracellular vesicles. 2024;13(2):e12404.
165. Shimizu Y, Inoue Y, Matsuura N, Ishii T, Sowa Y, Sunami H, et al Mesenchymal stromal cell–derived extracellular vesicles in regenerative medicine: Standardisation, bioengineering and clinical translation. Regenerative Therapy. 2026;31:101058.
2. Wesemann DR, Nagler CR. The microbiome, timing, and barrier function in the context of allergic disease. Immunity. 2016;44(4):728–38.
3. Li H, Tian Y, Xie L, Liu X, Huang Z, Su W. Mesenchymal stem cells in allergic diseases: Current status. Allergology International. 2020;69(1):35–45.
4. Asamoah F, Kakourou A, Dhami S, Lau S, Agache I, Muraro A, et al Allergen immunotherapy for allergic asthma: a systematic overview of systematic reviews. Clinical and translational allergy. 2017;7:1–12.
5. Papierniak ES, Lowenthal DT, Harman E. Novel therapies in asthma: leukotriene antagonists, biologic agents, and beyond. American journal of therapeutics. 2013;20(1):79–103.
6. Chesné J, Schmidt-Weber CB, von-Bieren JE. The use of adjuvants for enhancing allergen immunotherapy efficacy. Immunology and Allergy Clinics. 2016;36(1):125–45.
7. Cuppari C, Leonardi S, Manti S, Filippelli M, Alterio T, Spicuzza L, et al Allergen immunotherapy, routes of administration and cytokine networks: an update. Immunotherapy. 2014;6(6):775–86.
8. Sumi Y, Hamid Q. Airway remodeling in asthma. Allergology International. 2007;56(4):341–8.
9. Lung NH, Institute B, editors. Global initiative for asthma: global strategy for asthma management and prevention. NHLBI/WHO workshop report NHLBI publication; 1995.
10. Barnes PJ. New therapies for asthma: is there any progress? Trends in pharmacological sciences. 2010;31(7):335–43.
11. Singh D, Petavy F, Macdonald AJ, Lazaar AL, O'Connor BJ. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respiratory research. 2010;11:1–9.
12. Yazid S, Sinniah A, Solito E, Calder V, Flower RJ. Anti-allergic cromones inhibit histamine and eicosanoid release from activated human and murine mast cells by releasing Annexin A1. PLoS One. 2013;8(3):e58963.
13. Larché M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nature Reviews Immunology. 2006;6(10):761–71.
14. Dong L, Wang Y, Zheng T, Pu Y, Ma Y, Qi X, et al Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice. Stem Cell Research & Therapy. 2021;12:1–14.
15. Renesme L, Pierro M, Cobey KD, Mital R, Nangle K, Shorr R, et al Definition and characteristics of mesenchymal stromal cells in preclinical and clinical studies: a scoping review. Stem Cells Translational Medicine. 2022;11(1):44–54.
16. P De Miguel M, Fuentes-Julian S, Blazquez-Martinez A, Y Pascual C, A Aller M, Arias J, et al Immunosuppressive properties of mesenchymal stem cells: advances and applications. Current molecular medicine. 2012;12(5):574–91.
17. Le Blanc K, Ringden O. Immunomodulation by mesenchymal stem cells and clinical experience. Journal of internal medicine. 2007;262(5):509–25.
18. Markov A, Thangavelu L, Aravindhan S, Zekiy AO, Jarahian M, Chartrand MS, et al Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders. Stem cell research & therapy. 2021;12:1–30.
19. Genç D, Zibandeh N, Nain E, Gökalp M, Özen A, Göker M, et al Dental follicle mesenchymal stem cells down‐regulate Th2‐mediated immune response in asthmatic patients mononuclear cells. Clinical & Experimental Allergy. 2018;48(6):663–78.
20. Lin S-C, Liou Y-M, Ling T-Y, Chuang Y-H, Chiang B-L. Placenta-derived mesenchymal stem cells reduce the interleukin-5 level experimentally in children with asthma. International journal of medical sciences. 2019;16(11):1430.
21. Hofmann NA, Ortner A, Jacamo RO, Reinisch A, Schallmoser K, Rohban R, et al Oxygen sensing mesenchymal progenitors promote neo-vasculogenesis in a humanized mouse model in vivo. 2012.
22. Bell GI, Meschino MT, Hughes-Large JM, Broughton HC, Xenocostas A, Hess DA. Combinatorial human progenitor cell transplantation optimizes islet regeneration through secretion of paracrine factors. Stem cells and development. 2012;21(11):1863–76.
23. Zhao S, Wehner R, Bornhäuser M, Wassmuth R, Bachmann M, Schmitz M. Immunomodulatory properties of mesenchymal stromal cells and their therapeutic consequences for immune-mediated disorders. Stem cells and development. 2010;19(5):607–14.
24. Waszak P, Alphonse R, Vadivel A, Ionescu L, Eaton F, Thébaud B. Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. Stem cells and development. 2012;21(15):2789–97.
25. Dabrowska S, Andrzejewska A, Janowski M, Lukomska B. Immunomodulatory and regenerative effects of mesenchymal stem cells and extracellular vesicles: therapeutic outlook for inflammatory and degenerative diseases. Frontiers in immunology. 2021;11:591065.
26. Sun Y-Q, Deng M-X, He J, Zeng Q-X, Wen W, Wong DS, et al Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice. Stem cells. 2012;30(12):2692–9.
27. Abreu SC, Weiss DJ, Rocco PR. Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases? Stem cell research & therapy. 2016;7:1–10.
28. Hong GH, Kwon H-S, Lee KY, Ha EH, Moon K-A, Kim SW, et al hMSCs suppress neutrophil-dominant airway inflammation in a murine model of asthma. Experimental & molecular medicine. 2017;49(1):e288-e.
29. Trzil JE, Masseau I, Webb TL, Chang CH, Dodam JR, Cohn LA, et al Long‐term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma. Clinical & Experimental Allergy. 2014;44(12):1546–57.
30. Fu Y, Li J, Zhang Z, Ren F, Wang Y, Jia H, et al Umbilical cord mesenchymal stem cell‐derived exosomes alleviate collagen‐induced arthritis by balancing the population of Th17 and regulatory T cells. FEBS letters. 2022;596(20):2668–77.
31. Mo Y, Kang S-Y, Bang J-Y, Kim Y, Jeong J, Jeong E-M, et al Intravenous mesenchymal stem cell administration modulates monocytes/macrophages and ameliorates asthmatic airway inflammation in a murine asthma model. Molecules and cells. 2022;45(11):833–45.
32. Choi JY, Hur J, Jeon S, Jung CK, Rhee CK. Effects of human adipose tissue-and bone marrow-derived mesenchymal stem cells on airway inflammation and remodeling in a murine model of chronic asthma. Scientific Reports. 2022;12(1):12032.
33. Yao Y, Fan X-L, Jiang D, Zhang Y, Li X, Xu Z-B, et al Connexin 43-mediated mitochondrial transfer of iPSC-MSCs alleviates asthma inflammation. Stem cell reports. 2018;11(5):1120–35.
34. Royce SG, Mao W, Lim R, Kelly K, Samuel CS. iPSC‐and mesenchymoangioblast‐derived mesenchymal stem cells provide greater protection against experimental chronic allergic airways disease compared with a clinically used corticosteroid. The FASEB Journal. 2019;33(5):6402–11.
35. Fang S-B, Zhang H-Y, Jiang A-Y, Fan X-L, Lin Y-D, Li C-L, et al Human iPSC-MSCs prevent steroid-resistant neutrophilic airway inflammation via modulating Th17 phenotypes. Stem cell research & therapy. 2018;9:1–12.
36. Bentley JK, Popova AP, Bozyk PD, Linn MJ, Baek AE, Lei J, et al Ovalbumin sensitization and challenge increases the number of lung cells possessing a mesenchymal stromal cell phenotype. Respiratory Research. 2010;11:1–15.
37. Ou-Yang H-F, Huang Y, Hu X-B, Wu C-G. Suppression of allergic airway inflammation in a mouse model of asthma by exogenous mesenchymal stem cells. Experimental biology and medicine. 2011;236(12):1461–7.
38. Gao P, Zhou Y, Xian L, Li C, Xu T, Plunkett B, et al Functional effects of TGF-β1 on mesenchymal stem cell mobilization in cockroach allergen–induced asthma. The Journal of Immunology. 2014;192(10):4560–70.
39. Xu T, Zhou Y, Qiu L, Do DC, Zhao Y, Cui Z, et al Aryl hydrocarbon receptor protects lungs from cockroach allergen–induced inflammation by modulating mesenchymal stem cells. The Journal of Immunology. 2015;195(12):5539–50.
40. Yu X, Yu L, Guo B, Chen R, Qiu C. A narrative review of research advances in mesenchymal stem cell therapy for asthma. Annals of Translational Medicine. 2020;8(21).
41. Fu Q, Chow Y, Sun S, Zeng Q, Li H, Shi J, et al Mesenchymal stem cells derived from human induced pluripotent stem cells modulate T‐cell phenotypes in allergic rhinitis. Allergy. 2012;67(10):1215–22.
42. Li Y, Li H, Cao Y, Wu F, Ma W, Wang Y, et al Placenta-derived mesenchymal stem cells improve airway hyperresponsiveness and inflammation in asthmatic rats by modulating the Th17/Treg balance. Molecular medicine reports. 2017;16(6):8137–45.
43. Zeng SL, Wang LH, Li P, Wang W, Yang J. Mesenchymal stem cells abrogate experimental asthma by altering dendritic cell function. Molecular Medicine Reports. 2015;12(2):2511–20.
44. Brown JM, Nemeth K, Kushnir‐Sukhov NM, Metcalfe DD, Mezey E. Bone marrow stromal cells inhibit mast cell function via a COX2‐dependent mechanism. Clinical & Experimental Allergy. 2011;41(4):526–34.
45. Fan X, Xu Z-B, Li C-L, Zhang H-Y, Peng Y-Q, He B-X, et al Mesenchymal stem cells regulate type 2 innate lymphoid cells via regulatory T cells through ICOS-ICOSL interaction. Stem Cells. 2021;39(7):975–87.
46. Kim RL, Bang J-Y, Kim J, Mo Y, Kim Y, Lee C-G, et al Mesenchymal stem cells exert their anti-asthmatic effects through macrophage modulation in a murine chronic asthma model. Scientific Reports. 2022;12(1):9811.
47. Wang M, Zhao N, Wang C, Jin ZB, Zhang L. Immunomodulatory properties of mesenchymal stem cells: A potential therapeutic strategy for allergic rhinitis. Allergy. 2023;78(6):1425–40.
48. Ma S-Y, Zhao N, Cui L, Li Y, Zhang H, Wang J, et al Therapeutic effects of human pluripotent stem cell-derived mesenchymal stem cells on a murine model of acute Type-2-dominated airway inflammation. Stem Cell Reviews and Reports. 2022;18(8):2939–51.
49. Michaeloudes C, Li X, Mak JC, Bhavsar PK. Study of mesenchymal stem cell-mediated mitochondrial transfer in in vitro models of oxidant-mediated airway epithelial and smooth muscle cell injury. In Vitro Models for Stem Cell Therapy: Methods and Protocols. 2021:93–105.
50. Keyhanmanesh R, Rahbarghazi R, Aslani MR, Hassanpour M, Ahmadi M. Systemic delivery of mesenchymal stem cells condition media in repeated doses acts as magic bullets in restoring IFN-γ/IL-4 balance in asthmatic rats. Life sciences. 2018;212:30–6.
51. Keyhanmanesh R, Khodamoradi F, Rahbarghazi R, Rahbarghazi A, Rezaie J, Ahmadi M, et al Intra-tracheal delivery of mesenchymal stem cell-conditioned medium ameliorates pathological changes by inhibiting apoptosis in asthmatic rats. Molecular Biology Reports. 2022;49(5):3721–8.
52. Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, et al The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduction and Targeted Therapy. 2022;7(1):92.
53. Sun L, Sha J, Meng C, Zhu D. Mesenchymal stem cell‐based therapy for allergic rhinitis. Stem Cells International. 2020;2020(1):2367524.
54. Gao F, Chiu S, Motan D, Zhang Z, Chen L, Ji H, et al Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell death & disease. 2016;7(1):e2062-e.
55. Jiang W, Xu J. Immune modulation by mesenchymal stem cells. Cell proliferation. 2020;53(1):e12712.
56. Park I-S, Kim JH, Bae J-S, Kim D-K, Mo J-H. The supernatant of tonsil‐derived mesenchymal stem cell has antiallergic effects in allergic rhinitis mouse model. Mediators of Inflammation. 2020;2020(1):6982438.
57. Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature medicine. 2009;15(1):42–9.
58. Hyvärinen K, Holopainen M, Skirdenko V, Ruhanen H, Lehenkari P, Korhonen M, et al Mesenchymal stromal cells and their extracellular vesicles enhance the anti-inflammatory phenotype of regulatory macrophages by downregulating the production of interleukin (IL)-23 and IL-22. Frontiers in immunology. 2018;9:771.
59. Abumaree M, Al Jumah M, Kalionis B, Jawdat D, Al Khaldi A, Abomaray F, et al Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti-inflammatory M2 macrophages. Stem Cell Reviews and Reports. 2013;9:620–41.
60. Nemeth K, Keane-Myers A, Brown JM, Metcalfe DD, Gorham JD, Bundoc VG, et al Bone marrow stromal cells use TGF-β to suppress allergic responses in a mouse model of ragweed-induced asthma. Proceedings of the National Academy of Sciences. 2010;107(12):5652–7.
61. Zhong H, Fan X-L, Fang S-B, Lin Y-D, Wen W, Fu Q-L. Human pluripotent stem cell-derived mesenchymal stem cells prevent chronic allergic airway inflammation via TGF-β1-Smad2/Smad3 signaling pathway in mice. Molecular immunology. 2019;109:51–7.
62. Ge W, Jiang J, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2, 3-dioxygenase expression. Transplantation. 2010;90(12):1312–20.
63. Dai Y-Y, Ni S-Y, Ma K, Ma Y-S, Wang Z-S, Zhao X-L. Stem cells from human exfoliated deciduous teeth correct the immune imbalance of allergic rhinitis via Treg cells in vivo and in vitro. Stem Cell Research & Therapy. 2019;10:1–14.
64. Wang G, Cao K, Liu K, Xue Y, Roberts AI, Li F, et al Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells. Cell Death & Differentiation. 2018;25(7):1209–23.
65. Lee K, Ko E, Park Y. Adipose Tissue-Derived Mesenchymal Stem Cell Inhibits Osteoclast Differentiation through Tumor Necrosis Factor Stimulated Gene-6. Tissue Engineering and Regenerative Medicine. 2024;21(4):587–94.
66. Day AJ, Milner CM. TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties. Matrix Biology. 2019;78:60–83.
67. Mittal M, Tiruppathi C, Nepal S, Zhao Y-Y, Grzych D, Soni D, et al TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Proceedings of the National Academy of Sciences. 2016;113(50):E8151-E8.
68. Wortzel I, Dror S, Kenific CM, Lyden D. Exosome-Mediated Metastasis: Communication from a Distance. Dev Cell. 2019;49(3):347–60.
69. Liu P, Wang W, Wang F, Fan J, Guo J, Wu T, et al Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer. J Transl Med. 2023;21(1):40.
70. Oveili E, Vafaei S, Bazavar H, Eslami Y, Mamaghanizadeh E, Yasamineh S, et al The potential use of mesenchymal stem cells-derived exosomes as microRNAs delivery systems in different diseases. Cell Communication and Signaling. 2023;21(1):20.
71. Sun Y, Liu G, Zhang K, Cao Q, Liu T, Li J. Mesenchymal stem cells-derived exosomes for drug delivery. Stem cell research & therapy. 2021;12:1–15.
72. Cai J, Wu J, Wang J, Li Y, Hu X, Luo S, et al Extracellular vesicles derived from different sources of mesenchymal stem cells: therapeutic effects and translational potential. Cell & bioscience. 2020;10:1–14.
73. Lai RC, Yeo RWY, Tan KH, Lim SK. Exosomes for drug delivery — a novel application for the mesenchymal stem cell. Biotechnology Advances. 2013;31(5):543–51.
74. Riazifar M, Mohammadi MR, Pone EJ, Yeri A, Lasser C, Segaliny AI, et al Stem cell-derived exosomes as nanotherapeutics for autoimmune and neurodegenerative disorders. ACS nano. 2019;13(6):6670–88.
75. Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Molecular Therapy. 2015;23(5):812–23.
76. Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem cell research & therapy. 2016;7:1–13.
77. Yin K, Wang S, Zhao RC. Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomarker research. 2019;7:1–8.
78. Torregrosa Paredes P, Esser J, Admyre C, Nord M, Rahman Q, Lukic A, et al Bronchoalveolar lavage fluid exosomes contribute to cytokine and leukotriene production in allergic asthma. Allergy. 2012;67(7):911–9.
79. Masyuk AI, Masyuk TV, LaRusso NF. Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases. Journal of hepatology. 2013;59(3):621–5.
80. de Castro LL, Xisto DG, Kitoko JZ, Cruz FF, Olsen PC, Redondo PAG, et al Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma. Stem cell research & therapy. 2017;8:1–12.
81. Dong B, Wang C, Zhang J, Zhang J, Gu Y, Guo X, et al Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization. Stem Cell Research & Therapy. 2021;12:1–17.
82. Ferguson SW, Wang J, Lee CJ, Liu M, Neelamegham S, Canty JM, et al The microRNA regulatory landscape of MSC-derived exosomes: a systems view. Scientific reports. 2018;8(1):1419.
83. Xun C, Ge L, Tang F, Wang L, Zhuo Y, Long L, et al Insight into the proteomic profiling of exosomes secreted by human OM-MSCs reveals a new potential therapy. Biomedicine & Pharmacotherapy. 2020;131:110584.
84. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. science. 2020;367(6478):eaau6977.
85. Wu J, Kuang L, Chen C, Yang J, Zeng W-N, Li T, et al miR-100–5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. Biomaterials. 2019;206:87–100.
86. Zhao J, Li X, Hu J, Chen F, Qiao S, Sun X, et al Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovascular research. 2019;115(7):1205–16.
87. Cao J-Y, Wang B, Tang T-T, Wen Y, Li Z-L, Feng S-T, et al Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury. Theranostics. 2021;11(11):5248.
88. Wei H, Xu Y, Chen Q, Chen H, Zhu X, Li Y. Mesenchymal stem cell-derived exosomal miR-223 regulates neuronal cell apoptosis. Cell death & disease. 2020;11(4):290.
89. Han S, Ma C, Bao L, Lv L, Huang M. miR-146a mimics attenuate allergic airway inflammation by impacted group 2 innate lymphoid cells in an ovalbumin-induced asthma mouse model. International Archives of Allergy and Immunology. 2018;177(4):302–10.
90. Zhang X-H, Zhang Y-N, Li H-B, Hu C-Y, Wang N, Cao P-P, et al Overexpression of miR-125b, a novel regulator of innate immunity, in eosinophilic chronic rhinosinusitis with nasal polyps. American journal of respiratory and critical care medicine. 2012;185(2):140–51.
91. Bu X, Wang M, Luan G, Wang Y, Wang C, Zhang L, editors. Integrated miRNA and mRNA expression profiling reveals dysregulated miRNA‐mRNA regulatory networks in eosinophilic and non‐eosinophilic chronic rhinosinusitis with nasal polyps. International Forum of Allergy & Rhinology; 2021: Wiley Online Library.
92. Langwiński W, Szczepankiewicz D, Narożna B, Stegmayr J, Wagner D, Alsafadi H, et al Allergic inflammation in lungs and nasal epithelium of rat model is regulated by tissue-specific miRNA expression. Molecular Immunology. 2022;147:115–25.
93. Zhou Y, Zhang T, Yan Y, You B, You Y, Zhang W, et al MicroRNA-223–3p regulates allergic inflammation by targeting INPP4A. Brazilian Journal of Otorhinolaryngology. 2021;87(5):591–600.
94. Lyu B, Wei Z, Jiang L, Ma C, Yang G, Han S. MicroRNA-146a negatively regulates IL-33 in activated group 2 innate lymphoid cells by inhibiting IRAK1 and TRAF6. Genes & Immunity. 2020;21(1):37–44.
95. Li Z, Liu F, He X, Yang X, Shan F, Feng J. Exosomes derived from mesenchymal stem cells attenuate inflammation and demyelination of the central nervous system in EAE rats by regulating the polarization of microglia. International immunopharmacology. 2019;67:268–80.
96. Lopatina T, Bruno S, Tetta C, Kalinina N, Porta M, Camussi G. Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Communication and Signaling. 2014;12:1–12.
97. Yi X, Wei X, Lv H, An Y, Li L, Lu P, et al Exosomes derived from microRNA-30b-3p-overexpressing mesenchymal stem cells protect against lipopolysaccharide-induced acute lung injury by inhibiting SAA3. Experimental cell research. 2019;383(2):111454.
98. Lu F-B, Chen D-Z, Chen L, Hu E-D, Wu J-L, Li H, et al Attenuation of experimental autoimmune hepatitis in mice with bone mesenchymal stem cell-derived exosomes carrying microRNA-223–3p. Molecules and cells. 2019;42(12):906–18.
99. Du W, Zhang K, Zhang S, Wang R, Nie Y, Tao H, et al Enhanced proangiogenic potential of mesenchymal stem cell-derived exosomes stimulated by a nitric oxide releasing polymer. Biomaterials. 2017;133:70–81.
100. wei Li J, Wei L, Han Z, Chen Z. Mesenchymal stromal cells-derived exosomes alleviate ischemia/reperfusion injury in mouse lung by transporting anti-apoptotic miR-21–5p. European Journal of Pharmacology. 2019;852:68–76.
101. Gao S, Chen T, Hao Y, Zhang F, Tang X, Wang D, et al Exosomal miR-135a derived from human amnion mesenchymal stem cells promotes cutaneous wound healing in rats and fibroblast migration by directly inhibiting LATS2 expression. Stem Cell Research & Therapy. 2020;11:1–11.
102. Tao S-C, Guo S-C, Li M, Ke Q-F, Guo Y-P, Zhang C-Q. Chitosan wound dressings incorporating exosomes derived from microRNA-126-overexpressing synovium mesenchymal stem cells provide sustained release of exosomes and heal full-thickness skin defects in a diabetic rat model. Stem cells translational medicine. 2017;6(3):736–47.
103. Bunggulawa EJ, Wang W, Yin T, Wang N, Durkan C, Wang Y, et al Recent advancements in the use of exosomes as drug delivery systems. Journal of nanobiotechnology. 2018;16:1–13.
104. Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, et al Exosomes as drug delivery vehicles for Parkinson's disease therapy. Journal of controlled release. 2015;207:18–30.
105. Engeroff P, Vogel M. The Potential of Exosomes in Allergy Immunotherapy. Vaccines. 2022;10(1):133.
106. Shahir M, Mahmoud Hashemi S, Asadirad A, Varahram M, Kazempour‐Dizaji M, Folkerts G, et al Effect of mesenchymal stem cell‐derived exosomes on the induction of mouse tolerogenic dendritic cells. Journal of cellular physiology. 2020;235(10):7043–55.
107. Dehnavi S, Khodadadi A, Asadirad A, Ghadiri AA. Immune response modulation by allergen loaded into mesenchymal stem cell-derived exosomes as an effective carrier through sublingual immunotherapy. Immunobiology. 2023;228(3):152361.
108. Shahzad KA, Wang Z, Li X, Li J, Xu M, Tan F. Immunomodulatory effect of PLGA-encapsulated mesenchymal stem cells-derived exosomes for the treatment of allergic rhinitis. Frontiers in Immunology. 2024;15:1429442.
109. Fang S-B, Zhang H-Y, Meng X-C, Wang C, He B-X, Peng Y-Q, et al Small extracellular vesicles derived from human MSCs prevent allergic airway inflammation via immunomodulation on pulmonary macrophages. Cell death & disease. 2020;11(6):409.
110. Di Trapani M, Bassi G, Midolo M, Gatti A, Takam Kamga P, Cassaro A, et al Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions. Scientific reports. 2016;6(1):24120.
111. Fang S-B, Zhang H-Y, Wang C, He B-X, Liu X-Q, Meng X-C, et al Small extracellular vesicles derived from human mesenchymal stromal cells prevent group 2 innate lymphoid cell-dominant allergic airway inflammation through delivery of miR-146a-5p. Journal of extracellular vesicles. 2020;9(1):1723260.
112. Reis M, Mavin E, Nicholson L, Green K, Dickinson AM, Wang X-n. Mesenchymal stromal cell-derived extracellular vesicles attenuate dendritic cell maturation and function. Frontiers in immunology. 2018;9:2538.
113. Peng YQ, Deng XH, Xu ZB, Wu ZC, Fu QL. Mesenchymal stromal cells and their small extracellular vesicles in allergic diseases: From immunomodulation to therapy. European Journal of Immunology. 2023;53(10):2149510.
114. Zargar MJ, Kaviani S, Vasei M, Soufi Zomorrod M, Heidari Keshel S, Soleimani M. Therapeutic role of mesenchymal stem cell-derived exosomes in respiratory disease. Stem Cell Research & Therapy. 2022;13(1):194.
115. Hong D, Hu Z, Weng J, Yang L, Xiong Y, Liu Y. Effect of mesenchymal stem cell therapy in animal models of allergic rhinitis: A systematic review and meta-analysis. International Immunopharmacology. 2023;124:111003.
116. Dehnavi S, Khodadadi A, Asadirad A, Ghadiri A. Loading Ovalbumin into Mesenchymal Stem Cell-Derived Exosomes as a Nanoscale Carrier with Immunomodulatory Potential for Allergen-Specific Immunotherapy. Reports of Biochemistry & Molecular Biology. 2023;11(4):626.
117. Cruz FF, Borg ZD, Goodwin M, Sokocevic D, Wagner DE, Coffey A, et al Systemic administration of human bone marrow-derived mesenchymal stromal cell extracellular vesicles ameliorates aspergillus hyphal extract-induced allergic airway inflammation in immunocompetent mice. Stem cells translational medicine. 2015;4(11):1302–16.
118. Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organization Journal. 2015;8:1–12.
119. Wang M, Takeda K, Shiraishi Y, Okamoto M, Dakhama A, Joetham A, et al Peanut-induced intestinal allergy is mediated through a mast cell–IgE–FcεRI–IL-13 pathway. Journal of Allergy and Clinical Immunology. 2010;126(2):306–16. e12.
120. Cho K-S, Park M-K, Kang S-A, Park H-Y, Hong S-L, Park H-K, et al Adipose‐derived stem cells ameliorate allergic airway inflammation by inducing regulatory T cells in a mouse model of asthma. Mediators of Inflammation. 2014;2014(1):436476.
121. Dai R, Yu Y, Yan G, Hou X, Ni Y, Shi G. Intratracheal administration of adipose derived mesenchymal stem cells alleviates chronic asthma in a mouse model. BMC pulmonary medicine. 2018;18:1–9.
122. Kavanagh H, Mahon BP. Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells. Allergy. 2011;66(4):523–31.
123. Pai S, Muruganandah V, Kupz A. What lies beneath the airway mucosal barrier? Throwing the spotlight on antigen‐presenting cell function in the lower respiratory tract. Clinical & Translational Immunology. 2020;9(7):e1158.
124. Liu J, Zhang X, Cheng Y, Cao X. Dendritic cell migration in inflammation and immunity. Cellular & molecular immunology. 2021;18(11):2461–71.
125. Gazi U, Bahceciler NN. Immune mechanisms induced by sublingual immunotherapy in allergic respiratory diseases. Clin Exp Immunol. 2022;209(3):262–9.
126. Chiesa S, Morbelli S, Morando S, Massollo M, Marini C, Bertoni A, et al Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proceedings of the National Academy of Sciences. 2011;108(42):17384–9.
127. Mathias LJ, Khong SM, Spyroglou L, Payne NL, Siatskas C, Thorburn AN, et al Alveolar macrophages are critical for the inhibition of allergic asthma by mesenchymal stromal cells. The Journal of Immunology. 2013;191(12):5914–24.
128. Takeda K, Webb TL, Ning F, Shiraishi Y, Regan DP, Chow L, et al Mesenchymal stem cells recruit CCR2+ monocytes to suppress allergic airway inflammation. The Journal of Immunology. 2018;200(4):1261–9.
129. Wang X, Thomsen P. Mesenchymal stem cell–derived small extracellular vesicles and bone regeneration. Basic & clinical pharmacology & toxicology. 2021;128(1):18–36.
130. Lelek J, Zuba-Surma EK. Perspectives for future use of extracellular vesicles from umbilical cord-and adipose tissue-derived mesenchymal stem/stromal cells in regenerative therapies—synthetic review. International journal of molecular sciences. 2020;21(3):799.
131. Tieu A, Slobodian M, Fergusson DA, Montroy J, Burger D, Stewart DJ, et al Methods and efficacy of extracellular vesicles derived from mesenchymal stromal cells in animal models of disease: a preclinical systematic review protocol. Systematic reviews. 2019;8:1–8.
132. Du Y-m, Zhuansun Y-x, Chen R, Lin L, Lin Y, Li J-g. Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma. Experimental Cell Research. 2018;363(1):114–20.
133. Zhuansun Y, Du Y, Huang F, Lin L, Chen R, Jiang S, et al MSCs exosomal miR-1470 promotes the differentiation of CD4+ CD25+ FOXP3+ Tregs in asthmatic patients by inducing the expression of P27KIP1. International Immunopharmacology. 2019;77:105981.
134. Groß F, Metzner G, Behn U. Mathematical modeling of allergy and specific immunotherapy: Th1–Th2–Treg interactions. Journal of theoretical biology. 2011;269(1):70–8.
135. Amu S, Saunders SP, Kronenberg M, Mangan NE, Atzberger A, Fallon PG. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model. Journal of Allergy and Clinical Immunology. 2010;125(5):1114–24. e8.
136. van de Veen W. The role of regulatory B cells in allergen immunotherapy. Current opinion in allergy and clinical immunology. 2017;17(6):447–52.
137. Palomares O, Yaman G, Azkur AK, Akkoc T, Akdis M, Akdis CA. Role of Treg in immune regulation of allergic diseases. European journal of immunology. 2010;40(5):1232–40.
138. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–5.
139. Pavón-Romero GF, Parra-Vargas MI, Ramírez-Jiménez F, Melgoza-Ruiz E, Serrano-Pérez NH, Teran LM. Allergen Immunotherapy: Current and Future Trends. Cells. 2022;11(2).
140. Mirra V, Montella S, Santamaria F. Pediatric severe asthma: a case series report and perspectives on anti-IgE treatment. Bmc Pediatrics. 2018;18:1–11.
141. Senti G, Freiburghaus AU, Larenas-Linnemann D, Hoffmann HJ, Patterson AM, Klimek L, et al Intralymphatic Immunotherapy: Update and Unmet Needs. Int Arch Allergy Immunol. 2019;178(2):141–9.
142. Calderon M, Simons F, Malling HJ, Lockey R, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy. 2012;67(3):302–11.
143. Cox L. Sublingual immunotherapy and allergic rhinitis. Current Allergy and Asthma Reports. 2008;8(2):102–10.
144. Yukselen A, Kendirli SG. Role of immunotherapy in the treatment of allergic asthma. World J Clin Cases. 2014;2(12):859–65.
145. Burks AW, Calderon MA, Casale T, Cox L, Demoly P, Jutel M, et al Update on allergy immunotherapy: American academy of allergy, asthma & immunology/European academy of allergy and clinical immunology/PRACTALL consensus report. Journal of Allergy and Clinical Immunology. 2013;131(5):1288–96. e3.
146. Tsabouri S, Mavroudi A, Feketea G, Guibas GV. Subcutaneous and sublingual immunotherapy in allergic asthma in children. Frontiers in Pediatrics. 2017;5:82.
147. Calderón MA, Casale TB, Togias A, Bousquet J, Durham SR, Demoly P. Allergen-specific immunotherapy for respiratory allergies: from meta-analysis to registration and beyond. Journal of Allergy and Clinical Immunology. 2011;127(1):30–8.
148. Sadeghi M, Shahbaz SK, Dehnavi S, Koushki K, Sankian M. Current possibilities and future perspectives for improving efficacy of allergen-specific sublingual immunotherapy. International Immunopharmacology. 2021;101:108350.
149. Asadirad A, Ghadiri AA, Amari A, Ghasemi Dehcheshmeh M, Sadeghi M, Dehnavi S. Sublingual prophylactic administration of OVA-loaded MSC-derived exosomes to prevent allergic sensitization. International Immunopharmacology. 2023;120:110405.
150. Liu W, Ota M, Tabushi M, Takahashi Y, Takakura Y. Development of allergic rhinitis immunotherapy using antigen-loaded small extracellular vesicles. Journal of Controlled Release. 2022;345:433–42.
151. Firouzabadi SR, Mohammadi I, Ghafourian K, Kiani A, Hashemi SM. Mesenchymal stem cell-derived extracellular vesicle therapy for asthma in murine models: a systematic review and meta-analysis. Stem Cell Reviews and Reports. 2024;20(5):1162–83.
152. Chen S, Gao J, Zhang T. From mesenchymal stem cells to their extracellular vesicles: progress and prospects for asthma therapy. Asian Journal of Pharmaceutical Sciences. 2024;19(4):100942.
153. Wang W, Han ZC. Heterogeneity of human mesenchymal stromal/stem cells. Stem Cells Heterogeneity-Novel Concepts. 2019:165–77.
154. Moslehi D, Nahm WJ, Serwald G, Bigham Z, Nambudiri VE. Exosomes in precision dermatology: From biomarkers to targeted therapeutics in personalized care. Journal of the European Academy of Dermatology and Venereology. 2026.
155. Patel GK, Khan MA, Zubair H, Srivastava SK, Khushman Md, Singh S, et al Comparative analysis of exosome isolation methods using culture supernatant for optimum yield, purity and downstream applications. Scientific reports. 2019;9(1):5335.
156. Dai Y-Y, Ni S-Y, Ma K, Ma Y-S, Wang Z-S, Zhao X-L. Stem cells from human exfoliated deciduous teeth correct the immune imbalance of allergic rhinitis via Treg cells in vivo and in vitro. Stem Cell Research & Therapy. 2019;10(1):39.
157. Wenjin L, Yanjie W, Xueping Q, Yunfang A, Changqing Z. Research advances of mesenchymal stem cell in allergic rhinitis. Journal of Clinical Otorhinolaryngology Head and Neck Surgery. 2024;38(5):442.
158. Chattopadhyay S, Rajendran RL, Chatterjee G, Reyaz D, Prakash K, Hong CM, et al Mesenchymal stem cell-derived exosomes: a paradigm shift in clinical therapeutics. Experimental Cell Research. 2025;450(1):114616.
159. Schwarzenbach H, Gahan PB. Exosomes in immune regulation. Non-coding RNA. 2021;7(1):4.
160. Lotfy A, AboQuella NM, Wang H. Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials. Stem cell research & therapy. 2023;14(1):66.
161. Ma CY, Zhai Y, Li CT, Liu J, Xu X, Chen H, et al Translating mesenchymal stem cell and their exosome research into GMP compliant advanced therapy products: promises, problems and prospects. Medicinal research reviews. 2024;44(3):919–38.
162. Pan W, Chen H, Wang A, Wang F, Zhang X. Challenges and strategies: scalable and efficient production of mesenchymal stem cells-derived exosomes for cell-free therapy. Life sciences. 2023;319:121524.
163. Almeria C, Kreß S, Weber V, Egger D, Kasper C. Heterogeneity of mesenchymal stem cell-derived extracellular vesicles is highly impacted by the tissue/cell source and culture conditions. Cell & bioscience. 2022;12(1):51.
164. Welsh JA, Goberdhan DC, O'Driscoll L, Buzas EI, Blenkiron C, Bussolati B, et al Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. Journal of extracellular vesicles. 2024;13(2):e12404.
165. Shimizu Y, Inoue Y, Matsuura N, Ishii T, Sowa Y, Sunami H, et al Mesenchymal stromal cell–derived extracellular vesicles in regenerative medicine: Standardisation, bioengineering and clinical translation. Regenerative Therapy. 2026;31:101058.
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| Keywords | ||
| Allergic asthma Exosome Immunotherapy Mesenchymal stem cell (MSC) | ||
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How to Cite
1.
Shadian Zarsabzevar M, Charoghdoozi K, Balighi MJ, Khazaei Y, Ebrahimpour A, Dehnavi S, Sadeghi M. The Probable Role of Mesenchymal Stromal/Stem Cells and Their Exosomes in Improving Allergen Immunotherapy. Iran J Allergy Asthma Immunol. 2026;:1-18.
