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.

The importance of T cell-derived cytokines in post-kala-azar dermal leishmaniasis.

Infection with the same species of Leishmania (L)donovani causes different manifestations including visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL), indicating that the host-related immunological parameters perform a decisive role in the pathogenesis of diseases. As PKDL is a reservoir of the parasite, a better understanding of the host immune responses is necessary to restrict the L. donovani transmission. The proper local production of Th1 cell-related cytokines (including IFN-γ, TNF-α and IL-12), Th17 cell-derived cytokines (such as IL-17A, IL-17F and IL-22), and CD8+ cytotoxic T lymphocyte (CTL)-derived IFN-γ are protective against PKDL. However, dominant production of regulatory CD4+ T cell-derived cytokines (such as IL-10 and TGF-ß), Th2 cell-derived cytokines (such as IL-4/IL-13), M2 macrophage-derived cytokines (such as IL-4 and IL-10), keratinocyte-derived IL-10, regulatory CD8+ T cell-derived IL-10, and dendritic cell-derived IL-10, IL-27 and IL-21 can contribute to the parasite persistence and PKDL development. Understanding of the T cell-related cytokine network within PKDL lesions gives rise to novel insights concerning the role of each cytokine in the protection or susceptibility to disease. Manipulation of the cytokine network can be considered as an interesting immunotherapeutic strategy for the treatment of L. donovani-mediated PKDL.