Written by: Krystal, Chongqing Medical University
Expert review: Professor Li Jing, Affiliated Hospital of Jiangsu University
Recently, a review published in Frontiers in immunology summarized the application of the immune properties of mesenchymal stem cells in clinical diseases, indicating that mesenchymal stem cells have great significance and application prospects in the clinical treatment of acute graft-versus-host disease and acute respiratory distress syndrome [1].
Up to now, there have been a number of mesenchymal stem cell drugs approved for marketing internationally, and among these new mesenchymal stem cell drugs that have been listed or are under study, immunomodulatory properties are one of their main mechanisms. Based on immunomodulatory and regenerative properties, mesenchymal stem cells have been widely used in clinical treatment protocols for multisystem diseases.
Regulatory effect of mesenchymal stem cells on human epidemic systems
Mesenchymal stem cells (MSCs) have immunomodulatory and regenerative properties, and mesenchymal stem cell therapy is currently used in the clinical treatment of acute graft-versus-host disease (GvHD) in some countries.
The immunomodulatory and immunological properties of mesenchymal stem cells are diverse and affect almost every major part of the human immune system.
Figure 1 (from literature [1]):
Mesenchymal stem cells employ a wide range of anti-inflammatory and regenerative immunomodulatory mechanisms, including direct regulation by intrinsic immunomodulatory and regenerative molecules, vesicles and extracellular vesicles, and indirectly through favorable upregulation of mesenchymal stem cell-mediated innate and adaptive immune responses.
Mesenchymal stem cells have immunomodulatory effects on both the adaptive and innate immune systems. At the cellular level, mesenchymal stem cells increased the production of CD4+, CD25+ regulatory T cells, and IL-10. Mesenchymal stem cells have immune privileges and do not induce a strong immune response. But this is not really immune privilege but immune avoidance, with mesenchymal stem cells expressing normal levels of HLA class I molecules, while HLA class II molecules have low or absent levels.
Nonetheless, xenomeric and allogeneic mesenchymal stem cells do not persist for long after infusion, and only exist in circulation shortly after infusion, which is believed to be due in part to the lung interception effect [2]. Mesenchymal stem cells first return to the lungs after intravenous injection and exert a powerful local and systemic immunomodulatory effect on the host immune system.
Immunomodulatory effects are used to treat a variety of diseases
Based on the immunomodulatory properties of mesenchymal stem cells, they have been studied to improve acute respiratory distress syndrome (ARDS), graft-versus-host disease, etc. Mesenchymal stem cells play a role in the treatment of acute respiratory distress syndrome induced by the novel coronavirus. In addition, mesenchymal stem cell infusions are safe and well tolerated, and no major side effects have been found in multiple safety studies and meta-analyses.
01
# Transplant anti-host disease
Graft-versus-host disease is a common complication after allogeneic hematopoietic stem cell transplantation, where T lymphocytes from allogeneic hematopoietic stem cell transplant donors attack the recipient's organs and cause multisystem damage, with the main organs affected being the liver, skin, and gastrointestinal tract. There are two types of acute and chronic, and common clinical manifestations include maculopapular rash, abdominal cramps, and elevated serum bilirubin.
In one multicenter study, the two-year survival rate was 53 percent in patients with complete response to steroid-refractory acute graft-versus-host disease, while the two-year survival rate for partially responding and non-responders was 16 percent [3]. Studies based on mesenchymal stem cell therapy have shown a complete response rate of 64% in children and 47% in adult patients, so mesenchymal stem cell therapy is mainly used for pediatric treatment.
A Turkish study of 33 children found that mesenchymal stem cells induced a complete response in 18 patients (54 percent), a partial response in seven (21 percent), and no response in eight children (24 percent) [4]. The two-year survival rate was 63% in patients with complete or partial response (75%).
These data suggest partial efficacy of mesenchymal stem cells, particularly in the treatment of severe acute graft-versus-host disease in children.
The use of mesenchymal stem cells in chronic graft-versus-host disease is more limited than in acute graft-versus-host disease, and most preliminary studies using mesenchymal stem cells for the treatment of chronic graft-versus-host disease are conducted in adult patients.
A meta-analysis of 76 children and adults using mesenchymal stem cells showed an overall response rate of 66 percent, with 23 percent of those patients responding completely and an overall survival rate of 64 percent, suggesting that mesenchymal stem cells can improve survival [5].
In summary, there are far fewer data on mesenchymal stem cell therapy for chronic graft-versus-host disease than for acute graft-versus-host disease, but preliminary studies have shown that stem cell therapy is partially effective.
02
# Acute respiratory distress syndrome
Acute respiratory distress syndrome is a life-threatening lung disease with a high mortality rate. The syndrome includes acute hypoxic respiratory failure with bilateral pulmonary infiltrates associated with sepsis, pneumonia, shock, or aspiration. Acute lung injury and acute respiratory distress syndrome are characterized by rapid alveolar injury, inflammation, cytokine storms, and accumulation of neutrophils, which can lead to pulmonary edema, leading to severe hypoxemia and carbon dioxide buildup.
Mesenchymal stem cells have a significant anti-inflammatory effect and enter the lungs first after intravenous infusion, which can improve the cytokine storm induced by acute respiratory distress syndrome in the lungs.
Deaths from COVID-19 are mainly due to acute respiratory distress syndrome and significant coagulation dysfunction that leads to cardiovascular death with pulmonary and multi-organ failure. Studies have shown that after receiving mesenchymal stem cell therapy in 10 patients with COVID-19-induced acute respiratory distress syndrome, inflammatory cytokines (IL-6 and CRP) were significantly reduced, all patients had lung infiltrates disappeared, and 7 patients survived and were discharged from the hospital. Moreover, no toxicity or infusion-related adverse reactions were observed.
brief summary
Mesenchymal stem cells have a strong immunomodulatory and regenerative effect, have a good effect in the treatment of chronic and acute graft-versus-host disease and acute respiratory distress syndrome, and have a good safety profile compared with other conventional immunosuppressive drugs. With the continuous progress of clinical practice, the indications for mesenchymal stem cell therapy will continue to expand, and it is expected to make more developments in many areas of rheumatic inflammatory diseases, sepsis and septic shock, neuroinflammation and other acute inflammatory diseases.
bibliography:
[1] Ringdén, O., Moll, G., Gustafsson, B., & Sadeghi, B. (2022). Mesenchymal Stromal Cells for Enhancing Hematopoietic Engraftment and Treatment of Graft-Versus-Host Disease, Hemorrhages and Acute Respiratory Distress Syndrome. Frontiers in immunology, 13, 839844. https://doi.org/10.3389/fimmu.2022.839844
[2] Ko , O. N., Gerson, S. L., Cooper, B. W., Dyhouse, S. M., Haynesworth, S. E., Caplan, A. I., & Lazarus, H. M. (2000). Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 18(2), 307–316. https://doi.org/10.1200/JCO.2000.18.2.307
[3] Le Blanc, K., Frassoni, F., Ball, L., Locatelli, F., Roelofs, H., Lewis, I., Lanino, E., Sundberg, B., Bernardo, M. E., Remberger, M., Dini, G., Egeler, R. M., Bacigalupo, A., Fibbe, W., Ringdén, O., & Developmental Committee of the European Group for Blood and Marrow Transplantation (2008). Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet (London, England), 371(9624), 1579–1586. https://doi.org/10.1016/S0140-6736(08)60690-X
[4] Erbey, F., Atay, D., Akcay, A., Ovali, E., & Ozturk, G. (2016). Mesenchymal Stem Cell Treatment for Steroid Refractory Graft-versus-Host Disease in Children: A Pilot and First Study from Turkey. Stem cells international, 2016, 1641402. https://doi.org/10.1155/2016/1641402
[5] Morata-Tarifa, C., Macías-Sánchez, M., Gutiérrez-Pizarraya, A., & Sanchez-Pernaute, R. (2020). Mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease-a meta-analysis. Stem cell research & therapy, 11(1), 64. https://doi.org/10.1186/s13287-020-01592-z
[6] Matthay, M. A., Calfee, C. S., Zhuo, H., Thompson, B. T., Wilson, J. G., Levitt, J. E., Rogers, A. J., Gotts, J. E., Wiener-Kronish, J. P., Bajwa, E. K., Donahoe, M. P., McVerry, B. J., Ortiz, L. A., Exline, M., Christman, J. W., Abbott, J., Delucchi, K. L., Caballero, L., McMillan, M., McKenna, D. H., … Liu, K. D. (2019). 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, 7(2), 154–162. https://doi.org/10.1016/S2213-2600(18)30418-1