scholarly journals Impact of Placenta-Derived Mesenchymal Stem Cells Treatment on Patients with Severe Lung Injury Caused by COVID-19 Pneumonia: Clinical and Immunological Aspect

2021 ◽  
Author(s):  
Mei-Chuan Chen ◽  
Kevin Shu-Leung Lai ◽  
Ko-Ling Chien ◽  
Sing-Teck Teng ◽  
Yuh-Rong Lin ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
B Cells ◽  
Lung Injury ◽  
Immune Responses ◽  
Critically Ill ◽  
Treg Cells ◽  
Control Group ◽  
Current Standard

Abstract Background:The novel coronavirus disease 2019 (COVID-19) has been a global pandemic health issue since 30, January, 2020. Mortality rate was as high as more than 50% in critically ill patients. The Stem cell treatment is effective in refractory severe critically ill COVID-19 patients, but immune regulation mechanisms have not been reported well. Therefore, we evaluate the clinical efficacy and immune modulation of placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) in severe critically ill COVID-19 infection who are refractory to current standard therapies.Methods:Intravenous infusion of 1 × 107 MatriPlax was given to five severe COVID-19 patients at Day 0 and day 4. Serum inflammatory markers and immune profiles were studied at Day 0, 4 and 8. Clinical parameters and 28-days mortality were compared between treated group and control group.Results:The treatment group had no 28-days mortality and Murray’s lung injury score was significantly improved compared with control group. After treatment, Ferritin, C-reactive protein (CRP) and Lactate dehydrogenases (LDH) were significantly reduced and lymphopenia was improved. IL-6, IL-1β, IFN-γ and IL-2 were significantly decreased together with decrease in IL-10 reflecting decreasing intensity of inflammation. Immune cell profiles showed increase in CD4+ T cells (CD4+ naïve T cells, CD4+ memory T cells subtypes), Treg cells, CD19+ B cells (and CD19+ naive B cells, CD27+ switched B cells subtypes) and dendritic cells, and a significant decrease in CD14+ monocytes (and CD16- classical, CD16+ non-classical subtypes) monocytes as well as plasma/plasmablast cells. pc-MSCs treatment suppressed hyper-inflammatory states of innate immune responses to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoted CD4+ T cells and CD19+ B cells towards adaptive immune responses.Conclusion:The intravenous transplantation of Matriplax was safe and effective for severe critically ill COVID-19 patients, especially those who were refractory to current standard care and immunosuppressive therapies

Mesenchymal stem cells induce the expansion of regulatory T cells in abortion-prone mice

Reproduction ◽  
2021 ◽  
Author(s):  
Amir Salek Farrokhi ◽  
Amir-Hassan Zarnani ◽  
Fatemeh Rezaei kahmini ◽  
Seyed Mohammad Moazzeni
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
De Novo ◽  
Abortion Rate ◽  
Cellular Mechanisms ◽  
Inguinal Lymph Nodes

Recurrent pregnancy loss (RPL) is one of the most common complications of early pregnancy associated in most cases with local or systemic immune abnormalities such as the diminished proportion of regulatory T cells (Tregs). Mesenchymal stem cells (MSCs) have been shown to modulate immune responses by de novo induction and expansion of Tregs. In this study, we analyzed the molecular and cellular mechanisms involved in Treg-associated pregnancy protection following MSCs administration in an abortion-prone mouse mating. In a case-control study, syngeneic abdominal fat-derived MSCs were administered intraperitoneally (i.p) to the DBA/2-mated CBA/J female mice on day 4.5 of pregnancy. Abortion rate, Tregs proportion in spleen and inguinal lymph nodes, and Ho1, Foxp3, Pd1, and Ctla4 genes expression at the feto-maternal interface were then measured on day 13.5 of pregnancy using flow cytometry and quantitative RT- PCR, respectively. The abortion rate in MSCs-treated mice was significantly reduced and normalized to the level observed in normal pregnant animals. We demonstrated a significant induction of Tregs in inguinal lymph nodes but not in the spleen following MSCs administration. Administration of MSCs remarkably upregulated the expression of HO1, Foxp3, Pd1, and Ctla4 genes in both placenta and decidua. Here, we show that MSCs therapy could protect the fetus in the abortion-prone mice through Tregs expansion and up-regulation of Treg-related genes. These events could establish an immune-privileged microenvironment, which participates in regulation of detrimental maternal immune responses against the semi-allogeneic fetus.

scholarly journals Effect of Human Mesenchymal Stem Cells on Xenogeneic T and B Cells Isolated from Lupus-Prone MRL.Faslpr Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Hong Kyung Lee ◽  
Eun Young Kim ◽  
Hyung Sook Kim ◽  
Eun Jae Park ◽  
Hye Jin Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Human Mesenchymal Stem Cells ◽  
Preclinical Studies ◽  
Dependent Manner ◽  
T And B Cells

Systemic lupus erythematosus (SLE) is an autoimmune disease, which is characterized by hyperactivation of T and B cells. Human mesenchymal stem cells (hMSCs) ameliorate the progression of SLE in preclinical studies using lupus-prone MRL.Faslpr mice. However, whether hMSCs inhibit the functions of xenogeneic mouse T and B cells is not clear. To address this issue, we examined the in vitro effects of hMSCs on T and B cells isolated from MRL.Faslpr mice. Naïve hMSCs inhibited the functions of T cells but not B cells. hMSCs preconditioned with IFN-γ (i) inhibited the proliferation of and IgM production by B cells, (ii) attracted B cells for cell–cell interactions in a CXCL10-dependent manner, and (iii) inhibited B cells by producing indoleamine 2,3-dioxygenase. In summary, our data demonstrate that hMSCs exert therapeutic activity in mice in three steps: first, naïve hMSCs inhibit the functions of T cells, hMSCs are then activated by IFN-γ, and finally, they inhibit B cells.

scholarly journals Dynamic Tracking Human Mesenchymal Stem Cells Tropism following Smoke Inhalation Injury in NOD/SCID Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
MeiJuan Song ◽  
Qi Lv ◽  
XiuWei Zhang ◽  
Juan Cao ◽  
ShuLi Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Inhalation Injury ◽  
Scid Mice ◽  
Alveolar Epithelial Cells ◽  
Smoke Inhalation ◽  
Control Group ◽  
Smoke Inhalation Injury

Multiple preclinical evidences have supported the potential value of mesenchymal stem cells (MSCs) for treatment of acute lung injury (ALI). However, few studies focus on the dynamic tropism of MSCs in animals with acute lung injury. In this study, we track systemically transplanted human bone marrow-derived mesenchymal stem cells (hBMSCs) in NOD/SCID mice with smoke inhalation injury (SII) through bioluminescence imaging (BLI). The results showed that hBMSCs systemically delivered into healthy NOD/SCID mouse initially reside in the lungs and then partially translocate to the abdomen after 24 h. Compared with the uninjured control group treated with hBMSCs, higher numbers of hBMSCs were found in the lungs of the SII NOD/SCID mice. In both the uninjured and SII mice, the BLI signals in the lungs steadily decreased over time and disappeared by 5 days after treatment. hBMSCs significantly attenuated lung injury, elevated the levels of KGF, decreased the levels of TNF-αin BALF, and inhibited inflammatory cell infiltration in the mice with SII. In conclusion, our findings demonstrated that more systemically infused hBMSCs localized to the lungs in mice with SII. hBMSC xenografts repaired smoke inhalation-induced lung injury in mice. This repair was maybe due to the effect of anti-inflammatory and secreting KGF of hMSCs but not associated with the differentiation of the hBMSCs into alveolar epithelial cells.

scholarly journals ­ Apatinib combined with PD-L1 blockade synergistically enhances antitumor immune responses and promotes HEV formation in gastric cancer

2021 ◽  
Author(s):  
Yu Zhang ◽  
Fei Wang ◽  
Hao-ran Sun ◽  
Ya-kai Huang ◽  
Jian-peng Gao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Combination Therapy ◽  
Immune Responses ◽  
Cytotoxic T Cells ◽  
Antibody Therapy ◽  
Treg Cells ◽  
Cytotoxic T Cell ◽  
Immunocompetent Mice

Abstract Purpose Apatinib, an antiangiogenic drug, has showed beneficial effects only in a fraction of advanced gastric cancer (GC) patients. Given the recent success of immunotherapies, combination of apatinib with immune checkpoint inhibitor may provide sustained and potent antitumor responses. Methods Immunocompetent mice with subcutaneous MFC tumors grown were given combination of apatinib and anti-PD-L1 antibody therapy. GC tissues from patients undergoing curative resection in China were collected, and the density of HEVs, MSI status and tumor-infiltrated lymphocytes were analyzed by immunohistochemical staining. Results Combined apatinib and PD-L1 blockade therapy synergistically delayed tumor growth and increased survival in MFC-bearing immunocompetent mice. The combination therapy promoted antitumor immunity by increasing the ratio of CD8+ cytotoxic T cells to Foxp3+ Treg cells, the accumulation of CD20+ B cells and the Th1/Th2 cytokine ratio (IFN-γ/IL-10). The combination therapy induced the formation of HEVs through activation of LTβR signaling, thus promoting CD8+ cytotoxic T cell and CD20+ B cell infiltration in tumors. In clinical GC samples, the density of HEVs positively correlated with the intratumoral infiltration of CD8+ cytotoxic T cells and CD20+ B cells. MSI-high GC showed a higher density of HEVs, CD8+ cytotoxic T cells and CD20+ B cells than MSS/MSI-low GC. GC patients with high densities of HEVs, CD8+ cytotoxic T cells and CD20+ B cells had an improved prognosis with superior overall survival. Conclusion Combining apatinib with PD-L1 blockade treatment synergistically enhances antitumor immune responses and promotes HEV formation in GC.

Mesenchymal Stem Cells (MSC) Are Not Intrinsically Immune Privileged: Direct Demonstration in TCR Transgenic Mice and by Imaging of Allogeneic Luciferase+ MSC in Immune Competent Vs Immune Deficient Mice

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 549-549 ◽  
Author(s):  
Lior Zangi ◽  
Andreas Beilhack ◽  
Robert Negrin ◽  
Raanan Margalit ◽  
Yair Reisner
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Transgenic Mice ◽  
Cd8 T Cells ◽  
Immune Memory ◽  
Control Group ◽  
Allogeneic Bone ◽  
Donor Type

Abstract Mesenchymal stem cells (MSC) can induce a broad array of immunomodulating mechanisms. Furthermore, several studies have advocated that MSC can be transplanted across allogeneic barriers without eliciting an immune response. This notion was based on clinical case reports or animal studies using highly sensitive techniques such as polymerase chain reaction, fluorescent in-situ hybridization or enhanced green fluorescent protein, enabling detection of rare cells in different tissues. However, a recent study comparing syngeneic and allogeneic MSC demonstrated that while the former cells induced tolerance to allogeneic bone marrow (BM) the use of donor type allogeneic MSC was counteractive leading to enhanced rejection of the BM cells. Thus it was indicated for the first time that allogeneic MSC might induce immune memory rather than tolerance to donor type cells. In the present study we directly addressed this possibility by infusing intravenously MSC isolated from H2db (C57BLxBalb) F1 donors, into TCR transgenic mice (the 2C model, C57BL/6 background), in which CD8+ T cells express a TCR transgene against H2d. Mice in the control group were infused with phosphate buffered saline (PBS). Thirty days after the first immunization, the mice were re-challenged with MSC and 5 days later peripheral blood CD8+ T cells were examined by FACS for the acquisition of a memory phenotype (CD122+, CD44+ and CD62Llow). This assay revealed a significantly elevated level of memory CD8 T cells (6.7±0.45 %) in the re-challenged mice compared to that found in the control group of naïve mice (0.4 ± 0.5 %, P<0.01). Further evidence for induction of immune memory by MSC was directly demonstrated by non-invasive imaging of bone marrow derived MSC isolated from Luciferase+ (Luc+) transgenic FVB-L2G85 mice (MSC-Luc+). Thus, while MSC (0.9–1.8 *108 MSC/Kg) infused intravenously or intraperitonealy into immune competent Balb/c mice survived longer (27% survival at 35 days) compared to adult fibroblast (Fib-Luc+ ) (9% survival at 15 days, p<0.01), this prolonged survival of MSC is significantly shorter compared to that exhibited in immune deficient Balb-Nude and NOD-SCID recipients (100% survival at 120 days, p<0.01), indicating that the MSC cannot evade immune rejection although capable of delaying it. The enhanced survival of MSC in Balb-Nude mice strongly indicates that rejection of these cells in normal Balb/c mice is mediated by T cells. Remarkably, rejection was found upon infusion of about 100- fold more MSC, compared to the cell number, which can currently be generated ex-vivo for transplantation in humans (around 1*106/Kg). Infusion of a lower number of MSC (4 *107 MSC/Kg) was found to be even less effective (9% survival at 15 days, p<0.01). To define whether the allogeneic rejection of MSC-Luc+ or Fib-Luc+ is associated with induction of immune memory, we re-challenged mice previously rejecting 2*106 Fib-Luc+ or MSC-Luc+ cells, with Fib-Luc+ cells. Thus, 30 days after rejection of the first inoculums the recipients were implanted with a second transplant of 2*106 Fib-Luc+ cells. Our data reveals that graft rejection was significantly more rapid in re-transplanted Balb/c mice. While a significant density of Fib-Luc+ cells can be detected in all transplanted recipients at day two, survival at day 5 was reduced to 27% or 18% in mice primed with Fib or MSC, respectively, compared to 81% in naive recipients (p<0.01). Survival of Fib-Luc+ cells in re-challenged mice was further reduced at day 9 (9% or 0% in mice previously receiving Fib or MSC, respectively) compared to 72% survival in naive recipients, p<0.01). Collectively, these results demonstrate that MSC are not intrinsically immune privileged and under allogeneic settings these cells induce rejection, which is followed by an immune memory. Considering that the use of allogeneic or even a third party (‘off the shelf’) MSC is commonly advocated for a variety of clinical applications, our results strongly suggest that long term survival of allogeneic MSC likely represents a major challenge. Further studies attempting to overcome rejection of donor MSC in the context of hematopoietic stem cell transplantation or in conjunction with co-stimulatory blockade are warranted.

Lung-Resident Mesenchymal Stem Cells Promote Repair of LPS-Induced Acute Lung Injury via Regulating the Balance of Regulatory T cells and Th17 cells

Inflammation ◽  
2018 ◽  
Vol 42 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Linlin Wang ◽  
Meng Shi ◽  
Lin Tong ◽  
Jian Wang ◽  
Shimeng Ji ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Acute Lung Injury ◽  
Regulatory T Cells ◽  
Lung Injury ◽  
Th17 Cells
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