Placental Extract and Exosomes Derived from Pregnant Mice Attenuate the Development of Experimental Autoimmune Encephalomyelitis
-
Morteza Motallebnezhad
,
Shirin Taghizadeh
,
Tayebe Aghaie
,
Maryam Azimi
,
Ali-Akbar Salari
,
Mahmoud Bozorgmehr
,
Elahe Safari
,
Reza Falak
,
Mir-Hadi Jazayeri
Abstract
Placental extract (PE) and exosomes from pregnant mice appear to have immunomodulatory and neuroprotective effects. In this study, we assessed the potential therapeutic effects of PE and exosomes obtained from pregnant mice in experimental autoimmune encephalomyelitis (EAE) mouse models.
C57BL/6 mice, 8 to 12 weeks of age, were prepared and administered PE, exosomes, and glatiramer acetate (GA), as an FDA-approved treatment for multiple sclerosis (MS), after EAE induction. Thereafter, the therapeutic effects of treatment were evaluated by measuring the clinical courses of the mice as well as determining the number of regulatory T (Treg) cells using flow cytometry, cytokine levels, and microRNA-326 expression via real-time PCR.
GA, PE, and exosomes reduced clinical severity, the extent of spinal cord demyelination, and the infiltration of inflammatory cells into the spinal cord. The frequency of CD4+CD25+FoxP3+ Treg cells increased after treatment of EAE mice with GA, PE, and exosomes. The mRNA expression of the inflammatory cytokines (interleukin-17 and interferon-gamma), as well as miR-326 expression, decreased significantly in the EAE mice after treatment with GA and exosomes.
PE and exosomes from pregnant mice are involved in the modulation of Treg/Th17 balance and provide a therapeutic approach for MS. Further clinical studies will hopefully confirm the safety and efficacy of such treatments in MS patients.
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11. Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol. 2009;10(12):1252-9.
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14. Jazayeri MH, Nedaeinia R, Aghaie T, Motallebnezhad M. Human placental extract attenuates neurological symptoms in the experimental autoimmune encephalomyelitis model of multiple sclerosis-a putative approach in MS disease? Auto Immun Highlights. 2020;11(1):1-9.
15. Langer-Gould A, Garren H, Slansky A, Ruiz PJ, Steinman L. Late pregnancy suppresses relapses in experimental autoimmune encephalomyelitis: Evidence for a suppressive pregancy-related serum factor. J Immunol. 2002;169(2):1084-91.
16. Gatson NN, Williams JL, Powell ND, McClain MA, Hennon TR, Robbins PD, et al. Induction of pregnancy during established EAE halts progression of CNS autoimmune injury via pregnancy-specific serum factors. J Neuroimmunol. 2011;230(1-2):105-13.
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18. Tastan B, Tarakcioglu E, Birinci Y, Park Y, Genc S. Role of exosomal microRNAs in cell-to-cell communication. Methods Mol Biol; 2022. p. 269-92.
19. Clark K, Zhang S, Barthe S, Kumar P, Pivetti C, Kreutzberg N, et al. Placental mesenchymal stem cell-derived extracellular vesicles promote myelin regeneration in an animal model of multiple sclerosis. Cells. 2019;8(12):1497.
20. Liu J, Luo S, Yang J, Ren F, Zhao Y, Luo H, et al. The protective effect of sheep placental extract on concanavalin A-induced liver injury in mice. Molecules. 2019;24(1):28.
21. Tiwary S, Shukla D, Tripathi A, Agrawal S, Singh M, Shukla V. Effect of placental-extract gel and cream on non-healing wounds. J Wound Care. 2006;15(7):325-8.
22. Kim BY, Park HR, Shin JH, Kim SW, Kim SW. Human placental extract reduces allergic inflammation in a murine allergic rhinitis model. Laryngoscope. 2014;124(10):E399-E404.
23. Park JD, Lee S-I, Kim AR, Park JM, Shin S-Y, Shin JH, et al. The effect of human placental extract on rheumatoid arthritis in an animal model. Ann Rehabil Med. 2012;36(2):197.
24. Voisin JE, Kinsky RG, Voisin GA. Maternal alloimmune reactions towards the murine conceptus and graft-versus-host reaction (GVHR) II. Inhibition of priming by placental extracts. J Reprod Immunol. 1986;9(2):85-94.
25. Park JY, Byeon JH, Park S-W, Eun S-H, Chae KY, Eun B-L. Neuroprotective effect of human placental extract on hypoxic–ischemic brain injury in neonatal rats. Brain & development. 2013;35(1):68-74.
26. de Toledo A, Nomoto K, Hirano E, Tohda C. Horse Placental Extract Enhances Neurogenesis in the Presence of Amyloid β. Nutrients. 2021;13(5):1672.
27. Poletaev A, Arapov N. Rehabilitation of patients after stroke: new remedy? Pharmacology. 2006;3:73-9.
28. Skehel JM. Preparation of extracts from animal tissues. Methods Mol Biol. 2004. p. 15-20.
29. Majidi-Zolbanin J, Doosti M-H, Kosari-Nasab M, Salari A-A. Prenatal maternal immune activation increases anxiety-and depressive-like behaviors in offspring with experimental autoimmune encephalomyelitis. Neuroscience. 2015;294:69-81.
30. Begum-Haque S, Christy M, Ochoa-Reparaz J, Nowak EC, Mielcarz D, Haque A, et al. Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate. J Neuroimmunol. 2011;232(1-2):136-44.
31. Begum-Haque S, Sharma A, Kasper IR, Foureau DM, Mielcarz DW, Haque A, et al. Downregulation of IL-17 and IL-6 in the central nervous system by glatiramer acetate in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2008;204(1-2):58-65.
32. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3(6):1101-8.
33. Ramakrishnan K, Jayaraman V. Management of partial-thickness burn wounds by amniotic membrane: a cost-effective treatment in developing countries. Burns. 1997;23:S33-S6.
34. Gold-Aubert P, Chaumontet M, Capt M. An experimental study of the anti-inflammatory and anti-arthritic properties of a standardized placental extract. Int J Tissue React. 1981;3(3-4):155-65.
35. Rosenthal M. The application of an extract of human placenta in the treatment of rheumatic affections. Int J Tissue React. 1982;4(2):147-51.
36. LUBOWE II. TOPICAL USE OF PLACENTA‐EXTRACT GEL (NON‐ESTROGENIC) IN THE TREATMENT OF AGING SKIN. J Am Geriatr Soc. 1963;11(9):914-7.
37. Biswas T, Auddy B, Bhattacharya N, Bhattacharya S, Mukherjee B. Wound healing activity of human placental extracts in rats. Acta Pharmacol Sin. 2001;22(12):1113-6.
38. Van Walderveen M, Tas M, Barkhof F, Polman C, Frequin S, Hommes O, et al. Magnetic resonance evaluation of disease activity during pregnancy in multiple sclerosis. Neurology. 1994;44(2):327-.
39. Gregg C, Shikar V, Larsen P, Mak G, Chojnacki A, Yong VW, et al. White matter plasticity and enhanced remyelination in the maternal CNS. J Neurosci. 2007;27(8):1812-23.
40. Jadidi‐Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol. 2011;74(1):1-13.
2. Dema M, Eixarch H, Villar LM, Montalban X, Espejo C. Immunosenescence in multiple sclerosis: The identification of new therapeutic targets. Autoimmun Rev. 2021:102893.
3. Aghaie T, Jazayeri MH, Avan A, Anissian A, Salari AA. Gold nanoparticles and polyethylene glycol alleviate clinical symptoms and alter cytokine secretion in a mouse model of experimental autoimmune encephalomyelitis. IUBMB life. 2019;71(9):1313-21.
4. Zozulya AL, Wiendl H. The role of regulatory T cells in multiple sclerosis. Nat Clin Pract Neurol. 2008;4(7):384-98.
5. Nosratabadi R, Rastin M, Sankian M, Haghmorad D, Mahmoudi M. Hyperforin-loaded gold nanoparticle alleviates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells and upregulating regulatory T cells. Nanomedicine. 2016;12(7):1961-71.
6. Aharoni R, Eilam R, Stock A, Vainshtein A, Shezen E, Gal H, et al. Glatiramer acetate reduces Th-17 inflammation and induces regulatory T-cells in the CNS of mice with relapsing–remitting or chronic EAE. J Neuroimmunol. 2010;225(1-2):100-11.
7. Taghizadeh S, Motallebnezhad M, Aghaie T, Azimi M, Aghamajidi A, Salari A-A, et al. Anti-Caspr-conjugated gold nanoparticles emergence as a novel approach in the treatment of EAE animal model. Metab Brain Dis. 2022.
8. Pashangzadeh S, Motallebnezhad M, Vafashoar F, Khalvandi A, Mojtabavi N. Implications the Role of miR-155 in the Pathogenesis of Autoimmune Diseases. Front Immunol. 2021;12:1645.
9. Azimi M, Ghabaee M, Moghadasi AN, Noorbakhsh F, Izad M. Immunomodulatory function of Treg-derived exosomes is impaired in patients with relapsing-remitting multiple sclerosis. Immunol Res. 2018;66(4):513-20.
10. Azimi M, Ghabaee M, Moghadasi AN, Izad M. Altered expression of miR-326 in T cell-derived exosomes of patients with relapsing-remitting multiple sclerosis. Iran J Allergy Asthma Immunol. 2019:108-13.
11. Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol. 2009;10(12):1252-9.
12. Villoslada P, Steinman L. New targets and therapeutics for neuroprotection, remyelination and repair in multiple sclerosis. Expert Opin Investig Drugs. 2020;29(5):443-59.
13. Engler JB, Heckmann NF, Jäger J, Gold SM, Friese MA. Pregnancy enables expansion of disease-specific regulatory T cells in an animal model of multiple sclerosis. J Immunol. 2019;203(7):1743-52.
14. Jazayeri MH, Nedaeinia R, Aghaie T, Motallebnezhad M. Human placental extract attenuates neurological symptoms in the experimental autoimmune encephalomyelitis model of multiple sclerosis-a putative approach in MS disease? Auto Immun Highlights. 2020;11(1):1-9.
15. Langer-Gould A, Garren H, Slansky A, Ruiz PJ, Steinman L. Late pregnancy suppresses relapses in experimental autoimmune encephalomyelitis: Evidence for a suppressive pregancy-related serum factor. J Immunol. 2002;169(2):1084-91.
16. Gatson NN, Williams JL, Powell ND, McClain MA, Hennon TR, Robbins PD, et al. Induction of pregnancy during established EAE halts progression of CNS autoimmune injury via pregnancy-specific serum factors. J Neuroimmunol. 2011;230(1-2):105-13.
17. Williams JL, Gatson NN, Smith KM, Almad A, McTigue DM, Whitacre CC. Serum exosomes in pregnancy-associated immune modulation and neuroprotection during CNS autoimmunity. Expert Rev Clin Immunol. 2013;149(2):236-43.
18. Tastan B, Tarakcioglu E, Birinci Y, Park Y, Genc S. Role of exosomal microRNAs in cell-to-cell communication. Methods Mol Biol; 2022. p. 269-92.
19. Clark K, Zhang S, Barthe S, Kumar P, Pivetti C, Kreutzberg N, et al. Placental mesenchymal stem cell-derived extracellular vesicles promote myelin regeneration in an animal model of multiple sclerosis. Cells. 2019;8(12):1497.
20. Liu J, Luo S, Yang J, Ren F, Zhao Y, Luo H, et al. The protective effect of sheep placental extract on concanavalin A-induced liver injury in mice. Molecules. 2019;24(1):28.
21. Tiwary S, Shukla D, Tripathi A, Agrawal S, Singh M, Shukla V. Effect of placental-extract gel and cream on non-healing wounds. J Wound Care. 2006;15(7):325-8.
22. Kim BY, Park HR, Shin JH, Kim SW, Kim SW. Human placental extract reduces allergic inflammation in a murine allergic rhinitis model. Laryngoscope. 2014;124(10):E399-E404.
23. Park JD, Lee S-I, Kim AR, Park JM, Shin S-Y, Shin JH, et al. The effect of human placental extract on rheumatoid arthritis in an animal model. Ann Rehabil Med. 2012;36(2):197.
24. Voisin JE, Kinsky RG, Voisin GA. Maternal alloimmune reactions towards the murine conceptus and graft-versus-host reaction (GVHR) II. Inhibition of priming by placental extracts. J Reprod Immunol. 1986;9(2):85-94.
25. Park JY, Byeon JH, Park S-W, Eun S-H, Chae KY, Eun B-L. Neuroprotective effect of human placental extract on hypoxic–ischemic brain injury in neonatal rats. Brain & development. 2013;35(1):68-74.
26. de Toledo A, Nomoto K, Hirano E, Tohda C. Horse Placental Extract Enhances Neurogenesis in the Presence of Amyloid β. Nutrients. 2021;13(5):1672.
27. Poletaev A, Arapov N. Rehabilitation of patients after stroke: new remedy? Pharmacology. 2006;3:73-9.
28. Skehel JM. Preparation of extracts from animal tissues. Methods Mol Biol. 2004. p. 15-20.
29. Majidi-Zolbanin J, Doosti M-H, Kosari-Nasab M, Salari A-A. Prenatal maternal immune activation increases anxiety-and depressive-like behaviors in offspring with experimental autoimmune encephalomyelitis. Neuroscience. 2015;294:69-81.
30. Begum-Haque S, Christy M, Ochoa-Reparaz J, Nowak EC, Mielcarz D, Haque A, et al. Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate. J Neuroimmunol. 2011;232(1-2):136-44.
31. Begum-Haque S, Sharma A, Kasper IR, Foureau DM, Mielcarz DW, Haque A, et al. Downregulation of IL-17 and IL-6 in the central nervous system by glatiramer acetate in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2008;204(1-2):58-65.
32. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3(6):1101-8.
33. Ramakrishnan K, Jayaraman V. Management of partial-thickness burn wounds by amniotic membrane: a cost-effective treatment in developing countries. Burns. 1997;23:S33-S6.
34. Gold-Aubert P, Chaumontet M, Capt M. An experimental study of the anti-inflammatory and anti-arthritic properties of a standardized placental extract. Int J Tissue React. 1981;3(3-4):155-65.
35. Rosenthal M. The application of an extract of human placenta in the treatment of rheumatic affections. Int J Tissue React. 1982;4(2):147-51.
36. LUBOWE II. TOPICAL USE OF PLACENTA‐EXTRACT GEL (NON‐ESTROGENIC) IN THE TREATMENT OF AGING SKIN. J Am Geriatr Soc. 1963;11(9):914-7.
37. Biswas T, Auddy B, Bhattacharya N, Bhattacharya S, Mukherjee B. Wound healing activity of human placental extracts in rats. Acta Pharmacol Sin. 2001;22(12):1113-6.
38. Van Walderveen M, Tas M, Barkhof F, Polman C, Frequin S, Hommes O, et al. Magnetic resonance evaluation of disease activity during pregnancy in multiple sclerosis. Neurology. 1994;44(2):327-.
39. Gregg C, Shikar V, Larsen P, Mak G, Chojnacki A, Yong VW, et al. White matter plasticity and enhanced remyelination in the maternal CNS. J Neurosci. 2007;27(8):1812-23.
40. Jadidi‐Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol. 2011;74(1):1-13.
| Files | ||
| Issue | Vol 21 No 6 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i6.11525 | |
| Keywords | ||
| Exosome Experimental autoimmune encephalomyelitis Glatiramer acetate Multiple sclerosis Placental extract | ||
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How to Cite
1.
Motallebnezhad M, Taghizadeh S, Aghaie T, Azimi M, Salari A-A, Bozorgmehr M, Safari E, Falak R, Jazayeri M-H. Placental Extract and Exosomes Derived from Pregnant Mice Attenuate the Development of Experimental Autoimmune Encephalomyelitis. Iran J Allergy Asthma Immunol. 2022;21(6):657-669.
