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Yale Professor Argues That MSC-Derived Exosomes, Rather Than MSCs Themselves, May Be Superior Treatment for Cytokine Storm in COVID-19; Also Says Convalescent Plasma Contains Trillions of Exosomes with Unknown Effects and May Interfere with Antibodies

In an open-access article published online as an editorial in The Journal of Extracellular Vesicles on November 14, 2020, (https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.12004), Philip Askenase (photo), MD, Professor of Medicine and Pathology, Section of Rheumatology and Clinical Immunology, Department of Internal Medicine, Yale University School of Medicine, (and former 30-Year Chief of Allergy & Clinical Immunology at Yale), argues that, with regard to treatment of severe COVID-19 patients, mesenchymal stromal cell (MSC)-derived-exosomes, rather than MSCs themselves, are likely superior for therapy of the severe pneumonia and cytokine storm. The editorial is titled "COVID-19 Therapy with Mesenchymal Stromal Cells (MSC) and Convalescent Plasma Must Consider Exosome Involvement: Do the Exosomes in Convalescent Plasma Antagonize the Weak Immune Antibodies?" Dr. Askenase notes that MSCs are increasingly being used as possible treatments for COVID-19 and other serious conditions, but that their released exosomes are equivalent, safer, and more convenient. Dr. Askenase states that the exosomes themselves would thus be a better therapeutic choice versus the MSCs. In support of this assertion, he notes that many reports in the literature, and his group’s own data on treatment of spinal cord injury (PLoS One, 2018 Jan 2; 13(1):e0190358; doi: 10.1371/journal.pone.0190358) (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190358) showed that the release of exosomes from the in-vivo-systemically-administered MSCs is actually responsible for the MSC-associated beneficial effects. Furthermore, he emphasizes again that exosomes are simpler, safer, and clinically much more convenient compared to their parental MSCs. Concerning side effects in the context of COVID‐19, Dr. Askenase suggests that the known tendency of MSCs to intravascularly aggregate in the lungs, causing pulmonary dysfunction, might synergize with the pneumonia aspects of the disease. Further, he said, the tendency of MSCs to form peripheral vascular micro-aggregates might synergize with the vascular clots of the COVID‐19 disease process, causing more significant central and/or peripheral vascular insufficiency. In contrast, he notes that MSC-derived exosomes have none of these potential problems.

Dr. Askenase emphasizes the utility of use of MSC-derived exosomes rather than the MSCs themselves in COVID-19 treatment, stating strongly that “it is committing significant medial research oversight to use MSCs instead of their released exosomes that actually are responsible for the MSCs’ beneficial actions.”

In addition to arguing for the use of MSC-derived exosomes rather than MSCs themselves in the treatment of severe COVID-19, Dr. Askenase describes the need to seriously consider the exosome-related aspects of convalescent plasma therapy in the treatment of COVID-19. He points out that such plasma can contain trillions of exosomes, and yet no definitive investigation of the possible effects of these exosomes—positive and/or negative—has been carried out in this disease area. Clearly, such investigations are called for, Dr. Askenase suggests.

He notes that many of these blood plasma exosomes derive from activated immune-modulating cells and can likely function to transfer microRNAs (miRNAs) that may act epigenetically to influence important cell-mediated immunity in the convalescent plasma recipient response to the virus.

Because the antibodies in COVID-19 are often weak and can be non-essential compared to cell-mediated immunity, it is possible, he suggests, that these plasma exosomes may actually reduce the already weak effect(s) of the plasma antibodies, and that, if so, this therapy, which has increasingly been shown to have unexpected mild or no effects, may actually be improved by removal of these antagonistic exosomes. Firstly, pro-viral induced exosomes, likely present at the height of disease, may carry over into convalescent plasma. Secondly, exosomes with negative actions on effector immunity via expression check point inhibitory surface PD‐L1, or other co‐inhibitory receptors, as found in other infections, could be present. Thirdly, conditions could emulate the situation in Ebola infections, where induced host exosomes can express a viral encoded Ag that suppress effector T-cells, and thus, similarly, would have to be removed.

Dr. Askenase continues that there is already sufficient clinical evidence--such as the recovery of patients with known genetic antibody deficiencies, and of some patients on anti-CD19 anti-B cell therapy--to suggest that, in the case of COVID diseases, the antibodies actually have little effect. Alternatively, immune resistance in this disease may be principally due to T-cell mechanisms (chiefly cytotoxic T-cells, as is true in most viral illnesses), that likely are more directly affected by certain exosomes in convalescent plasma, including exosomes that influence the helper T-cells upon which the antibody responses depend.

Further, he states that COVID‐19 convalescent plasma has, thus far, shown remarkably weak beneficial effects in several completed and published studies, if compared to what was expected based on the results of many prior studies in other serious systemic viral diseases. This may be due to the increasingly documented dysfunctional immune response to this particular infection and resulting weak antibodies, that may be further impaired by contrary-acting exosomes, present in the convalescent plasma, that can negatively influence T-cell and antigen-presenting cell-mediated mechanisms.

Dr. Askenase maintains that pre-selection of convalescent plasma for both the best antibodies and evaluation of exosome effects looking to possibly remove negatively acting exosomes, might produce the most optimal convalescent plasma therapy for severely affected COVID‐19 patients. Alternatively, in some plasma the exosomes may have helpful effects and thus need to be retained as relevant to patient therapy. There indeed are several mechanisms by which exosomes exert positive effects on the interactions of effector T-cells and companion antigen-presenting cells, crucially by affecting events at the immune synapse cleft involved in antigen-specific, cellular, and humoral immune responses (Immunol Lett. 2019 May; 209:11-20, doi: 10.1016/j.imlet.2019.03.009) (https://pubmed.ncbi.nlm.nih.gov/30954509/).

Dr. Askenase closes by saying, “I am bringing attention to the newly recognized fact that convalescent plasma undoubtedly contains very biologically active exosomes mediating important aspects of the effects of this plasma therapy, and that, so far, have been completely ignored in currently planned, and claimed better scientifically conceived, studies of convalescent plasma therapy.”

With further regard to exosomes in convalescent plasma, Dr. Askenase states, “These companion immune- and virus-activated exosomes in billions per milliliter that undoubtedly play an important role in the effects of the plasma may be crucial to the outcome of convalescent plasma treatment of very sick patients with COVID‐19 syndromes.”

[Journal of Extracellular Vesicles article]