Investigation of the effect of IFN-γ/TNF-α-treated mesenchymal stem cells on Th9- and Treg cell-related parameters in a mouse model of ovalbumin-induced allergic asthma.

OBJECTIVE: Th9- and regulatory T (Treg) cells exert pro- and anti-allergic activity, respectively. Mesenchymal stem cell (MSC)-related immunomodulatory impacts can be enhanced by inflammatory cytokines. Here, the modulatory effects of IFN-γ/TNF-α-induced MSCs on Th9- and Treg cell-related parameters were investigated using an asthma model. METHODS: Allergic asthma was induced in BALB/c mice using sensitized and challenging with ovalbumin (OVA). The asthmatic groups were treated intraperitoneally with PBS, MSCs, IFN-γ-induced MSCs, TNF-α-induced MSCs and 'IFN-γ + TNF-α'-induced MSCs before the challenge phase. The mice were sacrificed 24 h after challenge. The serum IL-9 and IL-35 levels, as well as gene expression of IL-9, PU.1, IL-35-EBI3, and FOXP3 in the lung tissues were assessed using ELISA and real time-PCR, respectively. RESULTS: The differences of Th9 and Treg-related parameters were not significant between untreated asthmatic mice and those treated with non-induced MSCs. In comparison with untreated asthmatic group, treatment with IFN-γ-induced MSCs significantly reduced serum IL-9 levels, reduced lung expression of IL-9 and PU.1, while increasing serum IL-35 levels as well as lung expression of FOXP3; treatment with TNF-α-induced MSCs significantly reduced serum IL-9 levels as well as lung expression of IL-9, and treatment with 'IFN-γ + TNF-α'-induced MSCs, significantly modulated all investigated Th9 and Treg-related parameters. In comparison to mice treated with non-induced MSCs, serum IL-9 levels were remarkably decreased in mice treated with IFN-γ-induced and 'IFN-γ + TNF-α'-induced MSCs. CONCLUSIONS: IFN-γ-and 'IFN-γ + TNF-α' treated MSCs exerted almost comparable impacts, but were more efficient than TNF-α-exposed MSCs. Thus, IFN-γ alone can be sufficient to promote immunomodulatory effects of MSCs.

Lymphopenia an important immunological abnormality in patients with COVID-19: Possible mechanisms.

The lymphopenia as a major immunological abnormality occurs in the majority of severe COVID-19 patients, which is strongly associated with mortality rate. A low proportion of lymphocytes may express the main receptor for SARS-CoV-2, called angiotensin-converting enzyme 2 (ACE2). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can also use ACE2-independent pathways to enter lymphocytes. Both SARS-CoV-2- and immune-mediated mechanisms may contribute to the occurrence of lymphopenia through influencing the lymphocyte production, survival or tissue re-distribution. The metabolic and biochemical changes can also affect the production and survival of lymphocytes in COVID-19 patients. Lymphopenia can cause general immunosuppression and promote cytokine storm, both of them play an important role in the viral persistence, viral replication, multi-organ failure and eventually death. Here, a comprehensive view concerning the possible mechanisms that may lead to the lymphocyte reduction in COVID-19 patients is provided, while highlighting the potential intervention approaches to prevent lymphopenia.