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Introduction: Mesenchymal stromal cells (MSC) have well defined immunomodulatory properties including the suppression of lymphocyte proliferation and inhibition of dendritic cell (DC) maturation involving both cell contact and soluble factors. These properties have made MSC attractive candidates for cellular therapy. However, the mechanism underlying these characteristics remains unclear. This study sought to investigate the mechanisms by which MSC induce a regulatory environment. Method: Allogeneic bone marrow mesenchymal stromal cells were cultured with T cells or dendritic cells in the presence or absence of gamma secretase inhibitor to block Notch receptor signalling. T cells and dendritic cells were examined by flow cytometry for changes in phenotype marker expression. Stable knock down MSC were generated to examine the influence of Jagged 1 signalling by MSC. Both wildtype and knockdown MSC were subsequently used in vivo in an animal model of allergic airway inflammation. Results: The Notch ligand Jagged-1 was demonstrated to be involved in MSC expansion of regulatory T cells (Treg). Additionally, MSC-induced a functional semi-mature DC phenotype, which further required Notch signalling for the expansion of Treg. MSC, but not Jagged-1 knock down MSC, reduced pathology in a mouse model of allergic airway inflammation. Protection mediated by MSC was associated with enhanced Treg in the lung and significantly increased production of interleukin (IL)-10 in splenocytes re-stimulated with allergen. Significantly less Treg and IL-10 was observed in mice treated with Jagged-1 knock down MSC. Conclusions: The current study suggests that MSC-mediated immune modulation involves the education and expansion of regulatory immune cells in a Jagged-1 dependent manner and provides the first report of the importance of Jagged-1 signalling in MSC protection against inflammation in vivo. [ABSTRACT FROM AUTHOR]

Recent advances in cell based therapies for lung diseases and critical illnesses offer significant promise. Despite encouraging preclinical results, the translation of efficacy to the clinical settings have not been successful. One of the possible reasons for this is the lack of understanding of the complex interaction between mesenchymal stromal cells (MSCs) and the host environment. Other challenges for MSC cell therapies include cell sources, dosing, disease target, donor variability, and cell product manufacturing. Here we provide an overview on advances and current issues with a focus on MSC-based cell therapies for inflammatory acute respiratory distress syndrome varieties and other inflammatory lung diseases. [ABSTRACT FROM AUTHOR]

High level expression of the pro‐inflammatory cytokine macrophage migration inhibitory factor (MIF) has been associated with severe asthma. The role of MIF and its functional promotor polymorphism in innate immune training is currently unknown. Using novel humanized CATT7 MIF mice, this study is the first to investigate the effect of MIF on bone marrow‐derived macrophage (BMDM) memory after house dust mite (HDM) challenge. CATT7 BMDMs demonstrated a significant primed increase in M1 markers following HDM and LPS stimulation, compared to naive mice. This M1 signature was found to be MIF‐dependent, as administration of a small molecule MIF inhibitor, SCD‐19, blocked the induction of this pro‐inflammatory M1‐like phenotype in BMDMs from CATT7 mice challenged with HDM. Training naive BMDMs in vitro with HDM for 24 h followed by a rest period and subsequent stimulation with LPS led to significantly increased production of the pro‐inflammatory cytokine TNFα in BMDMs from CATT7 mice but not WT mice. Addition of the pan methyltransferase inhibitor MTA before HDM training significantly abrogated this effect in BMDMs from CATT7 mice, suggesting that HDM‐induced training is associated with epigenetic remodelling. These findings suggest that trained immunity induced by HDM is under genetic control, playing an important role in asthma patients with the high MIF genotypes (CATT6/7/8). [ABSTRACT FROM AUTHOR]

BACKGROUND: Routine tracheostomy care has traditionally been a shared responsibility between respiratory therapy, and nursing. Our large tertiary teaching medical center has a team of respiratory therapists whose primary responsibility is to round on tracheostomized patients admitted to the general floors, and to ensure the most appropriate and timely patient care. Trach care in our ICU has historically been provided by critical care nurses with no formal guidelines. In 2014 the respiratory department implemented new guidelines that shifted tracheostomy care responsibility from the ICU nurses to respiratory therapists. These guidelines included bedside trach care and formal communications with the multidisciplinary team regarding suture removal, trach down-sizing and other issues pertaining to transition to the general floors. Our group wanted to investigate whether these changes impacted outcomes. METHOD: After obtaining approval from our institutional review board, our team evaluated 112 tracheostomized patients. Data points collected included ICU days, hospital days, days till formal rehab, ventilator days, days till suture removal, days till first speaking valve trial, days till speech therapy consult, days till first tracheostomy mask trial and days till first ambulation. RESULTS: There were 56 patients in the pre-implementation group and 56 in the post. Median ICU days were 18.5 and 16.0 (-2.5) (p=0.18), hospital days 27 and 24.5 (-2.5) (p=0.06), Rehab days 19.0 and 17.0 (-2.0) (p=0.12), ventilator days 15.0 and 15.0 (no difference) (p=0.69), days till de- cannulation 17.0 and 22.0 (+5.0) (p=0.07), days till suture removal 7.0 and 6.0 (-1.0) (p = 0.91, days till first speaking valve trial 10.0 and 10.00 (no difference) (p=0.93), days till tracheostomy down-size 10.5 and 10.0 (-0.5) (p= 1.0), days till speech therapy consult 6.0 and 5.5 (-0.5) (p=0.58), days till first tracheostomy mask trial 2.0 and 3.5 (+1.5) (p=0.39) and days till first ambulation 18.0 and 14.5 (-3.5) (p=0.11). All groups were evaluated using Analyse-it statistical analysis software (UK) and two tailed t-test's. CONCLUSIONS: several parameters demonstrated positive changes that reached clinical significance but not statistical significance, (p < .05, 95% Cl). These included ICU days, hospital days, days till suture removal, rehab days, days till down-size, days till speech consult, and days till first ambulation. Further study will be needed to prove statistical significance. [ABSTRACT FROM AUTHOR]

Immunosuppressive ability in human MSC donors has been shown to be variable and may be a limiting factor in MSC therapeutic efficacy in vivo. The importance of cytokine activation of mesenchymal stromal cells (MSCs) to facilitate their immunosuppressive function is well established. This study sought to further understand the interactions between MSCs and the commonly used calcineurin inhibitor cyclosporine A (CsA). The existing literature regarding approaches that use MSCs and cyclosporine are conflicting regarding the effect of CsA on MSC potency and function. Here, we clearly demonstrate that when added at the same time as MSCs, CsA negatively affects MSC suppression of T cell proliferation. However, licencing MSCs with IFNγ before addition of CsA protects MSCs from this negative effect. Notably, adding CsA to MSCs after IFNγ pre-stimulation enhances MSC production of IDO. Mechanistically, we identified that CsA reduces SOCS1 expression to facilitate enhanced IDO production in IFNγ pre-stimulated MSCs. Importantly, CsA exposure to IFNγ pre-stimulated MSC before administration, significantly enhanced the potency of MSCs in a human relevant humanised mouse model of acute Graft versus Host Disease. In summary, this study identified a novel licencing strategy to enhance MSC potency in vitro and in vivo. [ABSTRACT FROM AUTHOR]