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Cytokine Overproduction and Immune System Dysregulation in alloHSCT and COVID-19 Patients.

ABSTRACT: The COVID-19 pathomechanism depends on (i) the pathogenicity of the virus, (ii) ability of the immune system to respond to the cytopathic effect of the virus infection, (iii) co-morbidities. Inflammatory cytokine production constitutes a hallmark of COVID-19 that is facilitated by inability of adaptive immunity to control virus invasion. The effect of cytokine release syndrome is deleterious, but the severity of it depends on other confounding factors: age and comorbidities. In this study, we analyze the literature data on the post-transplant course of allogeneic hematopoietic stem cell transplanted (alloHSCT) patients, which is affected by generated inflammatory cytokines. The sequence of events boosting cytokine production was analyzed in relation to clinical and laboratory data highlighting the impact of cytokine generation on the post-transplant course. The collected data were compared to those from studies on COVID-19 patients. The similarities are: (i) the damage/pathogen-associated molecular pattern (DAMP/PAMP) stage is similar except for the initiation hit being sterile in alloHSCT (toxic damage of conditioning regimen) and viral in COVID-19; (ii) genetic host-derived factors play a role; (iii) adaptive immunity fails, DAMP signal(s) increases, over-production of cytokines occurs; (iv) monocytes lacking HLADR expression emerge, being suppressor cells hampering adaptive immunity; (v) immune system homeostasis is broken, the patient's status deteriorates to bed dependency, leading to hypo-oxygenation and malnutrition, which in turn stimulates the intracellular alert pathways with vigorous transcription of cytokine genes. All starts with the interaction between DAMPs with appropriate receptors, which leads to the production of pro-inflammatory cytokines, the inflammatory process spreads, tissue is damaged, DAMPs are released and a vicious cycle occurs. Attempts to modify intracellular signaling pathways in patients with post-alloHSCT graft vs host disease have already been undertaken. The similarities documented in this study show that this approach may also be used in COVID-19 patients for tuning signal transduction processes to interrupt the cycle that powers the cytokine overproduction.

SUBMITTER: Lange A

PROVIDER: S-EPMC8206782 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and objectivesThe novel coronavirus disease 2019 (COVID-19) has been a pandemic health issue in 30 January 2020. The mortality rate is as high as 50% in critically ill patients. Stem cell therapy is effective for those who are refractory to standard treatments. However, the immune responses that underlie stem cell therapy have not been well reported, particularly, in patients associated with moderate to severe acute respiratory distress syndrome (ARDS).MethodsOn Days 0 and 4, an intravenous infusion of 2 × 107 placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) were administered to five severe COVID-19 patients refractory to current standard therapies. Peripheral blood inflammatory markers and immune profiles were determined by multi-parameter flow cytometry and studied at Days 0, 4, and 8. Clinical outcomes were also observed.ResultsNone of the pc-MSC treated patients experienced 28-day mortality compared with the control group and showed a significant improvement in the PaO2/FiO2 ratio, Murray's lung injury scores, reduction in serum ferritin, lactate dehydrogenase (LDH), and C-reactive protein (CRP) levels. The cytokine profiles also showed a reduction in IL-1β, IFN-γ, IL-2, and IL-6, and an increase in IL-13 and IL-5 type 2 cytokines within 7 days of therapy. Lymphopenia was also significantly improved after 7 days of treatment. Immune cell profiles showed an increase in the proportions of CD4+ T cells (namely, CD4+ naïve T cells and CD4+ memory T cell subtypes), Treg cells, CD19+ B cells (namely, CD19+ naïve B cells, CD27+ switched B cell subtypes) and dendritic cells, and a significant decrease in the proportion of CD14+ monocytes (namely, CD16- classical and CD16+ non-classical subtypes), and plasma/plasmablast cells. No adverse effects were seen at the serial follow-up visits for 2 months after initial therapy.Conclusionpc-MSCs therapy suppressed hyper-inflammatory states of the innate immune response to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoting CD4+ T cells and CD19+ B cells toward adaptive immune responses in severely critically ill COVID-19 patients with moderate to severe ARDS, especially those who were refractory to current standard care and immunosuppressive therapies.

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Cytokine Overproduction and Immune System Dysregulation in alloHSCT and COVID-19 Patients.

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