Specific Clinical and Immunological Changes Following Mesenchymal Stem Cell Transplantation in COVID-19–induced Acute Respiratory Distress Syndrome Patients: A Phase-I Clinical Trial
-
Najmeh Kaffash Farkhad
,
Alireza Sedaghat
,
Hamidreza Reihani
,
Amir Adhami Moghadam
,
Ahmad Bagheri Moghadam
,
Nayereh Khadem Ghaebi
,
Mohammad Ali Khodadoust
,
Amin Reza Nikpoor
,
Jalil Tavakol Afshari
Abstract
Acute respiratory distress syndrome (ARDS) is a systemic inflammation resulting from immune system overactivity. ARDS is also a fatal complication of COVID-19. Mesenchymal stem cells (MSCs) have immune modulatory properties. This study evaluated the safety and efficacy of three times transplantation of umbilical cord-derived MSCs (UC-MSCs) in terms of specific immunological and clinical changes in mild-to-moderate COVID-19-induced ARDS patients.
In this single-center, open-label, phase 1 clinical trial, 20 patients diagnosed with COVID-19 and mild-to-moderate ARDS were included and were divided into two groups: a control group receiving standard care and an intervention group receiving UC-MSC in addition to standard care. Three consecutive intravenous transplants of UC-MSC (1× cells/kg body weight per each transplant) were performed in the intervention group on days 1, 3, and 5. The biological assay was investigated four times (days 0, 5, 10, and 17).
UC-MSCs improved the patients' clinical and paraclinical parameters, including leukocytosis, lymphopenia, thrombocytopenia, and liver enzyme abnormalities compared to the control group. They also decreased pro-inflammatory lymphocytes (TH1 and TH17) and increased anti-inflammatory T lymphocytes. Cell therapy also reduced the mean fluorescence intensity (MFI) in overactivated CD8+ T cells.
These findings show that three UC-MSC injections could regulate a hyperactivated immune system in COVID-19-induced ARDS patients by decreasing the inflammatory T lymphocyte subset and can improve the patient's hematological condition and liver function. However, more studies are needed in this area.
1. Metcalfe SM. Mesenchymal stem cells and management of COVID-19 pneumonia. Medicine in drug discovery. 2020;5:100019.
2. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive care medicine. 2020;46(4):586-90.
3. Hu B, Guo H, Zhou P, Shi Z-L. Characteristics of SARS-CoV-2 and COVID-19. Nature Reviews Microbiology. 2020:1-14.
4. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. The Journal of clinical investigation. 2020;130(5):2620-9.
5. Yin Y, Wunderink RG. MERS, SARS and other coronaviruses as causes of pneumonia. Respirology. 2018;23(2):130-7.
6. Jesenak M, Brndiarova M, Urbancikova I, Rennerova Z, Vojtkova J, Bobcakova A, et al. Immune parameters and COVID-19 infection–associations with clinical severity and disease prognosis. Frontiers in cellular and infection microbiology. 2020;10:364.
7. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. Jama. 2020;323(11):1061-9.
8. Farkhad NK, Reihani H, Moghadam AA, Moghadam AB, Tavakol-Afshari J. Are Mesenchymal Stem Cells able to manage Cytokine Storm in COVID-19 patients? A review of recent studies. Regenerative therapy. 2021.
9. Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, et al. Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging and disease. 2020;11(2):216.
10. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The lancet. 2020;395(10229):1054-62.
11. Farkhad NK, Mahmoudi A, Mahdipour E. How similar are human mesenchymal stem cells derived from different origins? a review of comparative studies. Current stem cell research & therapy. 2021;16(8):980-93.
12. Farkhad NK, Mahmoudi A, Mahdipour E. Regenerative therapy by using mesenchymal stem cells-derived exosomes in COVID-19 treatment. The potential role and underlying mechanisms. Regenerative Therapy. 2022.
13. Tavakol-Afshari J, Boroumand AR, Farkhad NK, Moghadam AA, Sahab-Negah S, Gorji A. Safety and efficacy of bone marrow derived-mesenchymal stem cells transplantation in patients with amyotrophic lateral sclerosis. Regenerative Therapy. 2021;18:268-74.
14. Ghoryani M, Shariati-Sarabi Z, Tavakkol-Afshari J, Mohammadi M. The sufficient immunoregulatory effect of autologous bone marrow-derived mesenchymal stem cell transplantation on regulatory T cells in patients with refractory rheumatoid arthritis. Journal of immunology research. 2020;2020.
15. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. The Lancet. 2008;371(9624):1579-86.
16. Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes. 2008;57(7):1759-67.
17. Manchikanti L, Centeno CJ, Atluri S, Albers SL, Shapiro S, Malanga GA, et al. Bone marrow concentrate (BMC) therapy in musculoskeletal disorders: evidence-based policy position statement of American Society of Interventional Pain Physicians (ASIPP). Pain Physician. 2020:E85-E131.
18. Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. The Lancet Respiratory Medicine. 2015;3(1):24-32.
19. Liu KD, Wilson JG, Zhuo H, Caballero L, McMillan ML, Fang X, et al. Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome. Annals of Intensive Care. 2014;4(1):1-9.
20. Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. The Lancet Respiratory Medicine. 2019;7(2):154-62.
21. Chen X, Shan Y, Wen Y, Sun J, Du H. Mesenchymal stem cell therapy in severe COVID-19: A retrospective study of short-term treatment efficacy and side effects. The Journal of Infection. 2020;81(4):647.
22. Shu L, Niu C, Li R, Huang T, Wang Y, Huang M, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem cell research & therapy. 2020;11(1):1-11.
23. Organization WH. Clinical management of severe acute respiratory infection ( SARI) when COVID-19 disease is suspected: interim guidance, 13 March 2020. WHO 2020.
24. Kaffash Farkhad N, Sedaghat A, Reihani H, Adhami Moghadam A, Bagheri Moghadam A, Khadem Ghaebi N, et al. Mesenchymal stromal cell therapy for COVID-19-induced ARDS patients: a successful phase 1, control-placebo group, clinical trial. Stem Cell Research & Therapy. 2022;13(1):1-13.
25. Özdemir RBÖ, Özdemir AT, Sarıboyacı AE, Uysal O, Tuğlu Mİ, Kırmaz C. The investigation of immunomodulatory effects of adipose tissue mesenchymal stem cell educated macrophages on the CD4 T cells. Immunobiology. 2019;224(4):585-94.
26. Hashemian S-MR, Aliannejad R, Zarrabi M, Soleimani M, Vosough M, Hosseini S-E, et al. Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series. Stem cell research & therapy. 2021;12(1):1-12.
27. Liang B, Chen J, Li T, Wu H, Yang W, Li Y, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells: A case report. Medicine. 2020;99(31).
28. Guan W-j, Ni Z-y, Hu Y, Liang W-h, Ou C-q, He J-x, et al. Clinical characteristics of coronavirus disease 2019 in China. New England Journal of Medicine. 2020;382(18):1708-20.
29. Meng F, Xu R, Wang S, Xu Z, Zhang C, Li Y, et al. Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial. Signal Transduction and Targeted Therapy. 2020;5(1):1-7.
30. Zhang Y, Ding J, Ren S, Wang W, Yang Y, Li S, et al. Intravenous infusion of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells as a potential treatment for patients with COVID-19 pneumonia. Stem Cell Research & Therapy. 2020;11:1-6.
31. Cho KA, Woo SY, Seoh JY, Han HS, Ryu KH. Mesenchymal stem cells restore CCl4‐induced liver injury by an antioxidative process. Cell biology international. 2012;36(12):1267-74.
32. Tao J, Nie Y, Wu H, Cheng L, Qiu Y, Fu J, et al. Umbilical cord blood-derived mesenchymal stem cells in treating a critically ill COVID-19 patient. J Infection in Developing Countries. 2020;14(10).
33. Tang L, Jiang Y, Zhu M, Chen L, Zhou X, Zhou C, et al. Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19. Frontiers of medicine. 2020;14(5):664-73.
34. Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Frontiers in immunology. 2019;10:1191.
35. Le Blanc K, Pittenger M. Mesenchymal stem cells: progress toward promise. Cytotherapy. 2005;7(1):36-45.
36. Jason J, Inge K. Modulation of CD8 and CD3 by HIV or HIV antigens. Scandinavian Journal of Immunology. 2001;53(3):259-67.
37. Ganji A, Farahani I, Khansarinejad B, Ghazavi A, Mosayebi G. Increased expression of CD8 marker on T-cells in COVID-19 patients. Blood Cells, Molecules, and Diseases. 2020;83:102437.
38. Pearce L, Davidson SM, Yellon DM. The cytokine storm of COVID-19: a spotlight on prevention and protection. Expert Opinion on Therapeutic Targets. 2020;24(8):723-30.
39. Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nature Reviews Immunology. 2012;12(5):383-96.
40. Jiang X-X, Zhang Y, Liu B, Zhang S-X, Wu Y, Yu X-D, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood. 2005;105(10):4120-6.
41. Meng SS, Guo FM, Zhang XW, Chang W, Peng F, Qiu HB, et al. mTOR/STAT‐3 pathway mediates mesenchymal stem cell–secreted hepatocyte growth factor protective effects against lipopolysaccharide‐induced vascular endothelial barrier dysfunction and apoptosis. J Cell Bio. 2019;120(3):3637-50.
42. Li Z, Niu S, Guo B, Gao T, Wang L, Wang Y, et al. Stem cell therapy for COVID‐19, ARDS and pulmonary fibrosis. Cell proliferation. 2020;53(12):e12939.
43. Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal transduction and targeted therapy. 2021;6(1):1-9.
2. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive care medicine. 2020;46(4):586-90.
3. Hu B, Guo H, Zhou P, Shi Z-L. Characteristics of SARS-CoV-2 and COVID-19. Nature Reviews Microbiology. 2020:1-14.
4. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. The Journal of clinical investigation. 2020;130(5):2620-9.
5. Yin Y, Wunderink RG. MERS, SARS and other coronaviruses as causes of pneumonia. Respirology. 2018;23(2):130-7.
6. Jesenak M, Brndiarova M, Urbancikova I, Rennerova Z, Vojtkova J, Bobcakova A, et al. Immune parameters and COVID-19 infection–associations with clinical severity and disease prognosis. Frontiers in cellular and infection microbiology. 2020;10:364.
7. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. Jama. 2020;323(11):1061-9.
8. Farkhad NK, Reihani H, Moghadam AA, Moghadam AB, Tavakol-Afshari J. Are Mesenchymal Stem Cells able to manage Cytokine Storm in COVID-19 patients? A review of recent studies. Regenerative therapy. 2021.
9. Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, et al. Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging and disease. 2020;11(2):216.
10. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The lancet. 2020;395(10229):1054-62.
11. Farkhad NK, Mahmoudi A, Mahdipour E. How similar are human mesenchymal stem cells derived from different origins? a review of comparative studies. Current stem cell research & therapy. 2021;16(8):980-93.
12. Farkhad NK, Mahmoudi A, Mahdipour E. Regenerative therapy by using mesenchymal stem cells-derived exosomes in COVID-19 treatment. The potential role and underlying mechanisms. Regenerative Therapy. 2022.
13. Tavakol-Afshari J, Boroumand AR, Farkhad NK, Moghadam AA, Sahab-Negah S, Gorji A. Safety and efficacy of bone marrow derived-mesenchymal stem cells transplantation in patients with amyotrophic lateral sclerosis. Regenerative Therapy. 2021;18:268-74.
14. Ghoryani M, Shariati-Sarabi Z, Tavakkol-Afshari J, Mohammadi M. The sufficient immunoregulatory effect of autologous bone marrow-derived mesenchymal stem cell transplantation on regulatory T cells in patients with refractory rheumatoid arthritis. Journal of immunology research. 2020;2020.
15. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. The Lancet. 2008;371(9624):1579-86.
16. Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes. 2008;57(7):1759-67.
17. Manchikanti L, Centeno CJ, Atluri S, Albers SL, Shapiro S, Malanga GA, et al. Bone marrow concentrate (BMC) therapy in musculoskeletal disorders: evidence-based policy position statement of American Society of Interventional Pain Physicians (ASIPP). Pain Physician. 2020:E85-E131.
18. Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. The Lancet Respiratory Medicine. 2015;3(1):24-32.
19. Liu KD, Wilson JG, Zhuo H, Caballero L, McMillan ML, Fang X, et al. Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome. Annals of Intensive Care. 2014;4(1):1-9.
20. Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. The Lancet Respiratory Medicine. 2019;7(2):154-62.
21. Chen X, Shan Y, Wen Y, Sun J, Du H. Mesenchymal stem cell therapy in severe COVID-19: A retrospective study of short-term treatment efficacy and side effects. The Journal of Infection. 2020;81(4):647.
22. Shu L, Niu C, Li R, Huang T, Wang Y, Huang M, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem cell research & therapy. 2020;11(1):1-11.
23. Organization WH. Clinical management of severe acute respiratory infection ( SARI) when COVID-19 disease is suspected: interim guidance, 13 March 2020. WHO 2020.
24. Kaffash Farkhad N, Sedaghat A, Reihani H, Adhami Moghadam A, Bagheri Moghadam A, Khadem Ghaebi N, et al. Mesenchymal stromal cell therapy for COVID-19-induced ARDS patients: a successful phase 1, control-placebo group, clinical trial. Stem Cell Research & Therapy. 2022;13(1):1-13.
25. Özdemir RBÖ, Özdemir AT, Sarıboyacı AE, Uysal O, Tuğlu Mİ, Kırmaz C. The investigation of immunomodulatory effects of adipose tissue mesenchymal stem cell educated macrophages on the CD4 T cells. Immunobiology. 2019;224(4):585-94.
26. Hashemian S-MR, Aliannejad R, Zarrabi M, Soleimani M, Vosough M, Hosseini S-E, et al. Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series. Stem cell research & therapy. 2021;12(1):1-12.
27. Liang B, Chen J, Li T, Wu H, Yang W, Li Y, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells: A case report. Medicine. 2020;99(31).
28. Guan W-j, Ni Z-y, Hu Y, Liang W-h, Ou C-q, He J-x, et al. Clinical characteristics of coronavirus disease 2019 in China. New England Journal of Medicine. 2020;382(18):1708-20.
29. Meng F, Xu R, Wang S, Xu Z, Zhang C, Li Y, et al. Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial. Signal Transduction and Targeted Therapy. 2020;5(1):1-7.
30. Zhang Y, Ding J, Ren S, Wang W, Yang Y, Li S, et al. Intravenous infusion of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells as a potential treatment for patients with COVID-19 pneumonia. Stem Cell Research & Therapy. 2020;11:1-6.
31. Cho KA, Woo SY, Seoh JY, Han HS, Ryu KH. Mesenchymal stem cells restore CCl4‐induced liver injury by an antioxidative process. Cell biology international. 2012;36(12):1267-74.
32. Tao J, Nie Y, Wu H, Cheng L, Qiu Y, Fu J, et al. Umbilical cord blood-derived mesenchymal stem cells in treating a critically ill COVID-19 patient. J Infection in Developing Countries. 2020;14(10).
33. Tang L, Jiang Y, Zhu M, Chen L, Zhou X, Zhou C, et al. Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19. Frontiers of medicine. 2020;14(5):664-73.
34. Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Frontiers in immunology. 2019;10:1191.
35. Le Blanc K, Pittenger M. Mesenchymal stem cells: progress toward promise. Cytotherapy. 2005;7(1):36-45.
36. Jason J, Inge K. Modulation of CD8 and CD3 by HIV or HIV antigens. Scandinavian Journal of Immunology. 2001;53(3):259-67.
37. Ganji A, Farahani I, Khansarinejad B, Ghazavi A, Mosayebi G. Increased expression of CD8 marker on T-cells in COVID-19 patients. Blood Cells, Molecules, and Diseases. 2020;83:102437.
38. Pearce L, Davidson SM, Yellon DM. The cytokine storm of COVID-19: a spotlight on prevention and protection. Expert Opinion on Therapeutic Targets. 2020;24(8):723-30.
39. Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nature Reviews Immunology. 2012;12(5):383-96.
40. Jiang X-X, Zhang Y, Liu B, Zhang S-X, Wu Y, Yu X-D, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood. 2005;105(10):4120-6.
41. Meng SS, Guo FM, Zhang XW, Chang W, Peng F, Qiu HB, et al. mTOR/STAT‐3 pathway mediates mesenchymal stem cell–secreted hepatocyte growth factor protective effects against lipopolysaccharide‐induced vascular endothelial barrier dysfunction and apoptosis. J Cell Bio. 2019;120(3):3637-50.
42. Li Z, Niu S, Guo B, Gao T, Wang L, Wang Y, et al. Stem cell therapy for COVID‐19, ARDS and pulmonary fibrosis. Cell proliferation. 2020;53(12):e12939.
43. Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal transduction and targeted therapy. 2021;6(1):1-9.
| Files | ||
| Issue | Vol 21 No 6 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i6.11530 | |
| Keywords | ||
| Acute respiratory distress syndrome Immunological biomarkers Inflammation Lymphopenia Mesenchymal stem cells | ||
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How to Cite
1.
Kaffash Farkhad N, Sedaghat A, Reihani H, Adhami Moghadam A, Bagheri Moghadam A, Khadem Ghaebi N, Khodadoust MA, Nikpoor AR, Tavakol Afshari J. Specific Clinical and Immunological Changes Following Mesenchymal Stem Cell Transplantation in COVID-19–induced Acute Respiratory Distress Syndrome Patients: A Phase-I Clinical Trial. Iran J Allergy Asthma Immunol. 2022;21(6):687-703.
