Mesenchymal Stem Cell-derived Exosome; An Interesting Nanocarrier to Improve Allergen-specific Intranasal Immunotherapy
-
Sajad Dehnavi
,
Maryam Dadmanesh
,
Negin Hosseini Rouzbahani
,
Mahmood Karimi
,
Ali Asadirad
,
Mohammad Gholami
,
Khodayar Ghorban
Abstract
Increasing the efficacy of allergen-specific intranasal immunotherapy (INIT) has recently been the main goal of several studies to establish this route as a safe delivery method through mucosal pathways. In this case, the present study evaluated the potential of INIT using ovalbumin (OVA)-loaded mesenchymal stromal/stem cell (MSC)-derived exosomes (Exo-OVA) in an allergic asthma mouse model.
Together with control groups, sensitized Balb/c mice underwent intranasal immunotherapy with Exo-OVA (10 μg OVA per dose) for three consecutive weeks. Serum-specific immunoglobulin E (IgE) levels, transforming growth factor-beta (TGF-β), interleukin (IL)-4, and interferon-gamma (IFN-γ) production by cultured spleen cells, lung histopathologic analysis, and nasopharyngeal lavage fluid cellular examinations were then conducted.
The results showed that INIT using Exo-OVA significantly increased IFN-γ and TGF-β secretion, while allergen-specific IgE and IL-4 production were dramatically decreased compared to the control group receiving phosphate-buffered saline. In addition, the eosinophil and total cell counts in the nasopharyngeal lavage fluid were reduced, and inflammatory conditions and cell accumulation in lung tissue were ameliorated.
In conclusion, the Exo-OVA improved the INIT efficacy compared to free OVA. Therefore, this formulation could be introduced as an effective approach for immunomodulatory purposes with a shorter treatment duration and reduced side effects.
1. 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 Res Ther. 2021;12(1):1-17.
2. Srinivasan A, Sundar IK. Recent updates on the role of extracellular vesicles in the pathogenesis of allergic asthma. Extracell Vesicles Circ Nucl Acids. 2021;2(8):127.
3. Sadeghi M, Shahbaz SK, Dehnavi S, Koushki K, Sankian M. Current possibilities and future perspectives for improving efficacy of allergen-specific sublingual immunotherapy. Int Immunopharmacol. 2021;101(13):108350.
4. Dehnavi S, Azad FJ, Hoseini RF, Moazzen N, Tavakkol-Afshari J, Nikpoor AR, et al. A significant decrease in the gene expression of interleukin-17 following the administration of synbiotic in patients with allergic rhinitis who underwent immunotherapy: A placebo-controlled clinical trial. J Res Med Sci. 2019;24:51.
5. Shahbaz SK, Varasteh A-R, Koushki K, Ayati SH, Mashayekhi K, Sadeghi M, et al. Sublingual dendritic cells targeting by aptamer: Possible approach for improvement of sublingual immunotherapy efficacy. Int Immunopharmaco. 2020;85(15):106603.
6. Salmani A, Mohammadi M, Hosseini RF, Afshari JT, Fouladvand A, Dehnavi S, et al. A significant increase in expression of FOXP3 and IL-17 genes in patients with allergic rhinitis underwent accelerated rush immunotherapy. Iran J Basic Med Sci. 2019;22(9):989.
7. Farazuddin M, Landers JJ, Janczak KW, Lindsey HK, Finkelman FD, Baker Jr JR, et al. Mucosal Nanoemulsion Allergy Vaccine Suppresses Alarmin Expression and Induces Bystander Suppression of Reactivity to Multiple Food Allergens. Front Immunol. 2021:62.
8. 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.
9. Suzuki M, Yokota M, Kanemitsu Y, Min W-P, Ozaki S, Nakamura Y. Intranasal administration of regulatory dendritic cells is useful for the induction of nasal mucosal tolerance in a mice model of allergic rhinitis. World Allergy Organ J. 2020;13(8):100447.
10. Sadeghi M, Asadirad A, Koushki K, Shahbaz SK, Dehnavi S. Recent advances in improving intranasal allergen-specific immunotherapy; focus on delivery systems and adjuvants. Int Immunopharmacol. 2022;113(14):109327.
11. 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. J Nanobiotechnol. 2018;16(1):1-13.
12. Asadirad A, Baghaei K, Hashemi SM, Dehnavi S, Ghanbarian H, Mortaz E, et al. Dendritic cell immunotherapy with miR-155 enriched tumor-derived exosome suppressed cancer growth and induced antitumor immune responses in murine model of colorectal cancer induced by CT26 cell line. Int immunopharmacol. 2022;104(23):108493.
13. Ren J, Liu Y, Yao Y, Feng L, Zhao X, Li Z, et al. Intranasal delivery of MSC-derived exosomes attenuates allergic asthma via expanding IL-10 producing lung interstitial macrophages in mice. Int Immunopharmacol. 2021;91(23):107288.
14. Gholami M, Ghorban K, Sadeghi M, Dadmanesh M, Rouzbahani NH, Dehnavi S. Mesenchymal stem cells and allergic airway inflammation; a therapeutic approach to induce immunoregulatory responses. Int Immunopharmacol. 2023;120:110367.
15. 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. Rep Biochem Mol Biol. 2023;11(4):626.
16. 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.
17. Asadirad A, Ghadiri AA, Amari A, Dehcheshmeh MG, Sadeghi M, Dehnavi S. Sublingual prophylactic administration of OVA-loaded MSC-derived exosomes to prevent allergic sensitization. Int Immunopharmacol. 2023;120:110405.
18. Shahgordi S, Sankian M, Yazdani Y, Mashayekhi K, Ayati SH, Sadeghi M, et al. Immune responses modulation by curcumin and allergen encapsulated into PLGA nanoparticles in mice model of rhinitis allergic through sublingual immunotherapy. Int immunopharmacol. 2020;84:106525.
19. Koushki K, Varasteh A-R, Shahbaz SK, Sadeghi M, Mashayekhi K, Ayati SH, et al. Dc-specific aptamer decorated gold nanoparticles: A new attractive insight into the nanocarriers for allergy epicutaneous immunotherapy. Int J Pharm. 2020;584:119403.
20. Bielinska AU, O’Konek JJ, Janczak KW, Baker Jr JR. Immunomodulation of TH2 biased immunity with mucosal administration of nanoemulsion adjuvant. Vaccine. 2016;34(34):4017-24.
21. Moitra S, Datta A, Mondal S, Hazra I, Faruk SMO, Das PK, et al. Modulation of regulatory T cells by intranasal allergen immunotherapy in an experimental rat model of airway allergy. Int Immunopharmacol. 2017;47:9-19.
22. Durham SR, Penagos M. Sublingual or subcutaneous immunotherapy for allergic rhinitis? J Allergy Clin Immunol. 2016;137(2):339-49. e10.
23. Vicente S, Peleteiro M, Díaz-Freitas B, Sanchez A, González-Fernández Á, Alonso MJ. Co-delivery of viral proteins and a TLR7 agonist from polysaccharide nanocapsules: a needle-free vaccination strategy. J Control Release. 2013;172(3):773-81.
24. Ou J, Shi W, Xu Y, Tao Z. Intranasal immunization with DNA vaccine coexpressing Der p 1 and ubiquitin in an allergic rhinitis mouse model. Ann Allergy Asthma Immunol. 2014;113(6):658-65. e1.
25. Hu W, Ma L, Yang G, Zeng X, Liu J, Cheng B, et al. Der p2‑A20 DNA vaccine attenuates allergic inflammation in mice with allergic rhinitis. Mol Med Reports. 2019;20(6):4925-32.
26. Ballester M, Jeanbart L, De Titta A, Nembrini C, Marsland BJ, Hubbell JA, et al. Nanoparticle conjugation enhances the immunomodulatory effects of intranasally delivered CpG in house dust mite-allergic mice. Sci Reports. 2015;5(1):1-13.
27. Barreto E, Serra MF, Dos Santos RV, Dos Santos CEA, Hickmann J, Cotias AC, et al. Local administration of gold nanoparticles prevents pivotal pathological changes in murine models of atopic asthma. J Biomed Nanotechno. 2015;11(6):1038-50.
28. Chaisri U, Tungtrongchitr A, Indrawattana N, Meechan P, Phurttikul W, Tasaniyananda N, et al. Immunotherapeutic efficacy of liposome-encapsulated refined allergen vaccines against Dermatophagoides pteronyssinus allergy. PLoS One. 2017;12(11):e0188627.
29. Prangtaworn P, Chaisri U, Seesuay W, Mahasongkram K, Onlamoon N, Reamtong O, et al. Tregitope-linked refined allergen vaccines for immunotherapy in cockroach allergy. Sci Reports. 2018;8(1):1-16.
30. Hashemi SM, Hassan ZM, Hossein-Khannazer N, Pourfathollah AA, Soudi S. Investigating the route of administration and efficacy of adipose tissue-derived mesenchymal stem cells and conditioned medium in type 1 diabetic mice. Inflammopharmacology. 2020;28(2):585-601.
31. Nojehdehi S, Soudi S, Hesampour A, Rasouli S, Soleimani M, Hashemi SM. Immunomodulatory effects of mesenchymal stem cell–derived exosomes on experimental type‐1 autoimmune diabetes. J Cell Biochem. 2018;119(11):9433-43.
32. Kou M, Huang L, Yang J, Chiang Z, Chen S, Liu J, et al. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool? Cell Death Dis. 2022;13(7):580.
33. Cho K-S, Park M-K, Kang S, 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. Med Inflammation. 2014;2014.
34. 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 Dis. 2020;11(6):1-15.
35. 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. Exp Cell Res. 2018;363(1):114-20.
36. 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 Res Ther. 2017;8(1):1-12.
37. 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 Transl Med. 2015;4(11):1302-16.
38. Mun SJ, Kang S, Park H-K, Yu HS, Cho K-S, Roh H-J. Intranasally Administered Extracellular Vesicles from Adipose Stem Cells Have Immunomodulatory Effects in a Mouse Model of Asthma. Stem Cells Int. 2021;2021.
39. Liu W, Ota M, Tabushi M, Takahashi Y, Takakura Y. Development of allergic rhinitis immunotherapy using antigen-loaded small extracellular vesicles. J Control Release. 2022;345(87):433-42.
2. Srinivasan A, Sundar IK. Recent updates on the role of extracellular vesicles in the pathogenesis of allergic asthma. Extracell Vesicles Circ Nucl Acids. 2021;2(8):127.
3. Sadeghi M, Shahbaz SK, Dehnavi S, Koushki K, Sankian M. Current possibilities and future perspectives for improving efficacy of allergen-specific sublingual immunotherapy. Int Immunopharmacol. 2021;101(13):108350.
4. Dehnavi S, Azad FJ, Hoseini RF, Moazzen N, Tavakkol-Afshari J, Nikpoor AR, et al. A significant decrease in the gene expression of interleukin-17 following the administration of synbiotic in patients with allergic rhinitis who underwent immunotherapy: A placebo-controlled clinical trial. J Res Med Sci. 2019;24:51.
5. Shahbaz SK, Varasteh A-R, Koushki K, Ayati SH, Mashayekhi K, Sadeghi M, et al. Sublingual dendritic cells targeting by aptamer: Possible approach for improvement of sublingual immunotherapy efficacy. Int Immunopharmaco. 2020;85(15):106603.
6. Salmani A, Mohammadi M, Hosseini RF, Afshari JT, Fouladvand A, Dehnavi S, et al. A significant increase in expression of FOXP3 and IL-17 genes in patients with allergic rhinitis underwent accelerated rush immunotherapy. Iran J Basic Med Sci. 2019;22(9):989.
7. Farazuddin M, Landers JJ, Janczak KW, Lindsey HK, Finkelman FD, Baker Jr JR, et al. Mucosal Nanoemulsion Allergy Vaccine Suppresses Alarmin Expression and Induces Bystander Suppression of Reactivity to Multiple Food Allergens. Front Immunol. 2021:62.
8. 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.
9. Suzuki M, Yokota M, Kanemitsu Y, Min W-P, Ozaki S, Nakamura Y. Intranasal administration of regulatory dendritic cells is useful for the induction of nasal mucosal tolerance in a mice model of allergic rhinitis. World Allergy Organ J. 2020;13(8):100447.
10. Sadeghi M, Asadirad A, Koushki K, Shahbaz SK, Dehnavi S. Recent advances in improving intranasal allergen-specific immunotherapy; focus on delivery systems and adjuvants. Int Immunopharmacol. 2022;113(14):109327.
11. 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. J Nanobiotechnol. 2018;16(1):1-13.
12. Asadirad A, Baghaei K, Hashemi SM, Dehnavi S, Ghanbarian H, Mortaz E, et al. Dendritic cell immunotherapy with miR-155 enriched tumor-derived exosome suppressed cancer growth and induced antitumor immune responses in murine model of colorectal cancer induced by CT26 cell line. Int immunopharmacol. 2022;104(23):108493.
13. Ren J, Liu Y, Yao Y, Feng L, Zhao X, Li Z, et al. Intranasal delivery of MSC-derived exosomes attenuates allergic asthma via expanding IL-10 producing lung interstitial macrophages in mice. Int Immunopharmacol. 2021;91(23):107288.
14. Gholami M, Ghorban K, Sadeghi M, Dadmanesh M, Rouzbahani NH, Dehnavi S. Mesenchymal stem cells and allergic airway inflammation; a therapeutic approach to induce immunoregulatory responses. Int Immunopharmacol. 2023;120:110367.
15. 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. Rep Biochem Mol Biol. 2023;11(4):626.
16. 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.
17. Asadirad A, Ghadiri AA, Amari A, Dehcheshmeh MG, Sadeghi M, Dehnavi S. Sublingual prophylactic administration of OVA-loaded MSC-derived exosomes to prevent allergic sensitization. Int Immunopharmacol. 2023;120:110405.
18. Shahgordi S, Sankian M, Yazdani Y, Mashayekhi K, Ayati SH, Sadeghi M, et al. Immune responses modulation by curcumin and allergen encapsulated into PLGA nanoparticles in mice model of rhinitis allergic through sublingual immunotherapy. Int immunopharmacol. 2020;84:106525.
19. Koushki K, Varasteh A-R, Shahbaz SK, Sadeghi M, Mashayekhi K, Ayati SH, et al. Dc-specific aptamer decorated gold nanoparticles: A new attractive insight into the nanocarriers for allergy epicutaneous immunotherapy. Int J Pharm. 2020;584:119403.
20. Bielinska AU, O’Konek JJ, Janczak KW, Baker Jr JR. Immunomodulation of TH2 biased immunity with mucosal administration of nanoemulsion adjuvant. Vaccine. 2016;34(34):4017-24.
21. Moitra S, Datta A, Mondal S, Hazra I, Faruk SMO, Das PK, et al. Modulation of regulatory T cells by intranasal allergen immunotherapy in an experimental rat model of airway allergy. Int Immunopharmacol. 2017;47:9-19.
22. Durham SR, Penagos M. Sublingual or subcutaneous immunotherapy for allergic rhinitis? J Allergy Clin Immunol. 2016;137(2):339-49. e10.
23. Vicente S, Peleteiro M, Díaz-Freitas B, Sanchez A, González-Fernández Á, Alonso MJ. Co-delivery of viral proteins and a TLR7 agonist from polysaccharide nanocapsules: a needle-free vaccination strategy. J Control Release. 2013;172(3):773-81.
24. Ou J, Shi W, Xu Y, Tao Z. Intranasal immunization with DNA vaccine coexpressing Der p 1 and ubiquitin in an allergic rhinitis mouse model. Ann Allergy Asthma Immunol. 2014;113(6):658-65. e1.
25. Hu W, Ma L, Yang G, Zeng X, Liu J, Cheng B, et al. Der p2‑A20 DNA vaccine attenuates allergic inflammation in mice with allergic rhinitis. Mol Med Reports. 2019;20(6):4925-32.
26. Ballester M, Jeanbart L, De Titta A, Nembrini C, Marsland BJ, Hubbell JA, et al. Nanoparticle conjugation enhances the immunomodulatory effects of intranasally delivered CpG in house dust mite-allergic mice. Sci Reports. 2015;5(1):1-13.
27. Barreto E, Serra MF, Dos Santos RV, Dos Santos CEA, Hickmann J, Cotias AC, et al. Local administration of gold nanoparticles prevents pivotal pathological changes in murine models of atopic asthma. J Biomed Nanotechno. 2015;11(6):1038-50.
28. Chaisri U, Tungtrongchitr A, Indrawattana N, Meechan P, Phurttikul W, Tasaniyananda N, et al. Immunotherapeutic efficacy of liposome-encapsulated refined allergen vaccines against Dermatophagoides pteronyssinus allergy. PLoS One. 2017;12(11):e0188627.
29. Prangtaworn P, Chaisri U, Seesuay W, Mahasongkram K, Onlamoon N, Reamtong O, et al. Tregitope-linked refined allergen vaccines for immunotherapy in cockroach allergy. Sci Reports. 2018;8(1):1-16.
30. Hashemi SM, Hassan ZM, Hossein-Khannazer N, Pourfathollah AA, Soudi S. Investigating the route of administration and efficacy of adipose tissue-derived mesenchymal stem cells and conditioned medium in type 1 diabetic mice. Inflammopharmacology. 2020;28(2):585-601.
31. Nojehdehi S, Soudi S, Hesampour A, Rasouli S, Soleimani M, Hashemi SM. Immunomodulatory effects of mesenchymal stem cell–derived exosomes on experimental type‐1 autoimmune diabetes. J Cell Biochem. 2018;119(11):9433-43.
32. Kou M, Huang L, Yang J, Chiang Z, Chen S, Liu J, et al. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool? Cell Death Dis. 2022;13(7):580.
33. Cho K-S, Park M-K, Kang S, 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. Med Inflammation. 2014;2014.
34. 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 Dis. 2020;11(6):1-15.
35. 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. Exp Cell Res. 2018;363(1):114-20.
36. 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 Res Ther. 2017;8(1):1-12.
37. 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 Transl Med. 2015;4(11):1302-16.
38. Mun SJ, Kang S, Park H-K, Yu HS, Cho K-S, Roh H-J. Intranasally Administered Extracellular Vesicles from Adipose Stem Cells Have Immunomodulatory Effects in a Mouse Model of Asthma. Stem Cells Int. 2021;2021.
39. Liu W, Ota M, Tabushi M, Takahashi Y, Takakura Y. Development of allergic rhinitis immunotherapy using antigen-loaded small extracellular vesicles. J Control Release. 2022;345(87):433-42.
| Files | ||
| Issue | Vol 22 No 6 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i6.14645 | |
| Keywords | ||
| Allergen immunotherapy Exosomes Immunomodulation Mesenchymal stromal cell Nanoparticle drug delivery system | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Dehnavi S, Dadmanesh M, Hosseini Rouzbahani N, Karimi M, Asadirad A, Gholami M, Ghorban K. Mesenchymal Stem Cell-derived Exosome; An Interesting Nanocarrier to Improve Allergen-specific Intranasal Immunotherapy. Iran J Allergy Asthma Immunol. 2023;22(6):561-574.
