Research and application progress in adoptive re-transfusion of regulatory cells in organ transplantation / 器官移植

Rejection and adverse reactions caused by long-term use of immunosuppressants severely affect the survival rate and quality of life of organ transplant recipients. Immune tolerance induction plays a key role in improving the survival rate and quality of life of organ transplant recipients. In recent years, tremendous progress has been achieved in adoptive re-transfusion of regulatory cells. In this article, research progress in regulatory T cell (Treg), myeloid-derived suppressor cell (MDSC) and regulatory B cell (Breg) in animal experiment and clinical application was reviewed, and the main clinical problems of adoptive re-transfusion of regulatory cells, the application of chimeric antigen receptor Treg and the concept of cell therapy in immune evaluation were summarized, aiming to deepen the understanding of regulatory cell therapy, promote the application of regulatory cells in immune tolerance of organ transplantation, and improve clinical efficacy of organ transplantation and the quality of life of recipients.

Kinetics of MDSC in Patients Treated Steroids-Ruxolitinib as the First Line Therapy for aGVHD / 中国实验血液学杂志

OBJECTIVE@#To analyze the kinetic characteristics of lymphocyte subsets and myeloid-derived suppressor cell (MDSC) in patients who newly diagnosed intermediate- to high-risk aGVHD and treated with steroids-ruxolitinib as the first line therapy from a single-arm, open clinical trial (NCT04061876).@*METHODS@#We prospectively observed the efficacy of 23 patients having intermediate- to high-risk aGVHD and treated with steroids-ruxolitinib as the first line therapy. The kinetic characteristics of lymphocyte subsets and MDSC were monitored, and then we compared them in steroids-ruxolitinib group (n=23), free-aGVHD group (n=20) and steroids group (n=23).@*RESULTS@#Of the 23 patients, the CR rate was 78.26% (18/23) on day 28 after first-line treatment with steroids-ruxolitinib. On day 28 after treatment, patients had lower level of CD4+CD29+ T cells (P=0.08) than that of pre-treatment, whereas levels of other lymphocyte subsets in this study were higher than that of pre-treatment; CD4+CD29+ T cells in CR patients decreased, compared with refractory aGVHD patients. On day 28 of treatment, CD8+CD28- T cells (P=0.03) significantly increased in patients with aGVHD than that in patients without aGVHD, so did CD8+CD28- T / CD8+CD28+ T cell ratio (P=0.03). Compared with patients without aGVHD, patients with aGVHD had lower level of G-MDSC, especially on day 14 after allo-HSCT (P=0.04). Compared with pre-treatment, M-MDSC was higher in CR patients on day 3 and 7 post-treatment (P3=0.01, P7=0.03), e-MDSC was higher on day 28 post-treatment (P=0.01). Moreover, compared with CR patients, M-MDSC was lower in refractory aGVHD patients on day 3 post-treatment (P=0.01) and e-MDSC was lower on day 28 post-treatment (P=0.01). Compared with steroids group, MDSC in steroids-ruxolitinib group was higher, with the most significant difference in M-MDSC (P3=0.0351; P7=0.0142; P14=0.0369).@*CONCLUSION@#We found that patients newly diagnosed intermediate- to high-risk aGVHD receiving first-line therapy with steroids-ruxolitinib achieved high response rate. Moreover, the novel first-line therapy has a small impact on the immune reconstitution of patients after allo-HSCT. Elevated MDSC might predict a better response in aGVHD patients receiving this novel first-line therapy. M-MDSC responded earlier to steroids-ruxolitinib than e-MDSC, G-MDSC.

Research advances of myeloid-derived suppressor cells in sepsis-induced immunosuppression / 中华危重病急救医学

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Most patients with sepsis underwent a state of immune suppression after surviving the acute inflammatory response, and were susceptible to secondary nosocomial infections, leading to a prolonged hospitalization and increased mortality rate. Myeloid-derived suppressor cells (MDSCs), a heterogeneous population with immunosuppressive activities, can contribute to the development of immunosuppression in patients with cancer and inhibit the host immune response, but the characteristics of MDSCs and their functional mechanism has not been fully addressed in the development of sepsis-induced immunosuppression. Thus, this review will summary the new findings on the mechanisms of MDSCs in septic immunosuppressionin order to provide ideas and directions for targeting MDSCs as treatment of septic immunosuppression.

Recent advances on the role of various cells-derived exosomes in ocular surface / 中华实验眼科杂志

Exosomes are membranous vesicles secreted by cells and can be widely involved in intercellular communication, anti-inflammation, immunoregulation, etc.Mesenchymal stem cell (MSC), regulatory T cell (Treg), immature dendritic cell (imDC) and myeloid-derived suppressor cell (MDSC) are the main ocular surface-related exosomes origins.Exosomes derived from different cells play their roles by delivering different biological molecules to recipient cells.Exosomes derived from MSC play a positive role in ocular surface inflammation and immune-related diseases by inhibiting T cell proliferation, transforming macrophage phenotype, regulating T helper (Th) cell differentiation and up-regulating Treg expression, reduce neovascularization and inflammation, and foster a microenvironment to promote corneal wound healing at the same time.Exosomes derived from Treg contain inducible NO synthase and microRNA (miRNA) including miR-503, miR-330 and miR-9, which can interfere with cell cycle progression, induce apoptosis, induce the differentiation of other T cells into Treg phenotype, inhibit T cell allograft rejection to induce immune tolerance.Exosomes derived from imDC inhibit corneal allograft rejection by delivering miR-682.MDSC-derived exosomes promote Treg expansion in vivo and in vitro, inhibit the proliferation and cytotoxicity of activated T cells, and express miR-29a-3p and miR-93-5p, which can inhibit the differentiation of Th1 and Th17 cells.Given the anti-inflammatory and immunosuppressive effects of exosomes, this paper reviewed the studies on ocular surface inflammation and immune-related diseases such as corneal injury, mucopolysaccharide storage disease, dry eye, Sj?gren syndrome and ocular graft-versus-host disease.

Characteristics of amino acid metabolism in myeloid-derived suppressor cells in septic mice / 北京大学学报(医学版)

OBJECTIVE@#To explore the amino acid metabolomics characteristics of myeloid-derived suppressor cells (MDSCs) in mice with sepsis induced by the cecal ligation and puncture (CLP).@*METHODS@#The sepsis mouse model was prepared by CLP, and the mice were randomly divided into a sham operation group (sham group, n = 10) and a CLP model group (n = 10). On the 7th day after the operation, 5 mice were randomly selected from the surviving mice in each group, and the bone marrow MDSCs of the mice were isolated. Bone marrow MDSCs were separated to measure the oxygen consumption rate (OCR) by using Agilent Seahorse XF technology and to detect the contents of intracellular amino acids and oligopeptides through ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) technology. Different metabolites and potential biomarkers were analyzed by univariate statistical analysis and multivariate statistical analysis. The major metabolic pathways were enriched using the small molecular pathway database (SMPDB).@*RESULTS@#The proportion of MDSCs in the bone marrow of CLP group mice (75.53% ± 6.02%) was significantly greater than that of the sham group (43.15%± 7.42%, t = 7.582, P < 0.001), and the basal respiratory rate [(50.03±1.20) pmol/min], maximum respiration rate [(78.07±2.57) pmol/min] and adenosine triphosphate (ATP) production [(25.30±1.21) pmol/min] of MDSCs in the bone marrow of CLP group mice were significantly greater than the basal respiration rate [(34.53±0.96) pmol/min, (t = 17.41, P < 0.001)], maximum respiration rate [(42.57±1.87) pmol/min, (t = 19.33, P < 0.001)], and ATP production [(12.63±0.96) pmol/min, (t = 14.18, P < 0.001)] of sham group. Leucine, threonine, glycine, etc. were potential biomarkers of septic MDSCs (all P < 0.05). The increased amino acids were mainly enriched in metabolic pathways, such as malate-aspartate shuttle, ammonia recovery, alanine metabolism, glutathione metabolism, phenylalanine and tyrosine metabolism, urea cycle, glycine and serine metabolism, β-alanine metabolism, glutamate metabolism, arginine and proline metabolism.@*CONCLUSION@#The enhanced mitochondrial oxidative phosphorylation, malate-aspartate shuttle and alanine metabolism in MDSCs of CLP mice may provide raw materials for mitochondrial aerobic respiration, thereby promoting the immunosuppressive function of MDSCs. Blocking the above metabolic pathways may reduce the risk of secondary infection in sepsis and improve the prognosis.

Changes and significance of granulocyte-like myeloid-derived suppressor cells during acute phase of Kawasaki disease / 中华微生物学和免疫学杂志

Objective:To investigate the changes and significance of granulocyte-like myeloid-derived suppressor cells (G-MDSC) in the acute phage of Kawasaki disease (KD).Methods:Forty-two children with acute KD were enrolled in the present study and 32 age-matched healthy children were selected as control group. The proportion of HLA-DR -CD11b + CD33 + CD14 -CD15 + G-MDSC, the concentration of reactive oxygen species (ROS) and the expression of arginase-1 (Arg-1), programmed death-ligand 1 (PD-L1), cytotoxic T lymphocyte associated protein 4 (CTLA4), glycoprotein 130 (gp130) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) at protein level were detected by flow cytometry. Quantitative real-time PCR was used to measure the expression of inducible nitric oxide synthase (iNOS), interferon regulatory factor 8 (IRF-8), IL-6 receptor α subunit (IL-6Rα), granulocyte colony-stimulating factor receptor (G-CSFR), CCAAT/enhancer binding protein β (C/EBPβ), suppressor of cytokine signaling 1 (SOCS1) and SOCS3 at mRNA level in G-MDSC. Chromatin immunoprecipitation was performed to detect the acetylation of histone H3 at the promoters of SOCS1 and SOCS3 genes. Plasma concentrations of IL-6 and granulocyte colony-stimulating factor (G-CSF) and protein levels of IL-10, transforming growth factor-β (TGF-β) and nitric oxide (NO) in the culture supernatant of G-MDSC stimulated with LPS were measured by ELISA. Results:(1) Compared with the control group, the proportion of HLA-DR -CD11b + CD33 + CD14 -CD15 + G-MDSC as well as the concentration of ROS and the expression of inhibitory molecules (Arg-1, PD-L1 and CTLA4) in G-MDSC increased significantly in patients with acute KD ( P<0.05). Moreover, the concentrations of IL-10 and TGF-β in culture supernatant of G-MDSC were also higher than those of the control group after stimulation with lipopolysaccharide for 48 h ( P<0.05). All of the seven afore-mentioned indexes in KD patients with coronary artery lesion (CAL group ) were lower than those in patients without coronary artery lesion (NCAL group) ( P<0.05), and restored to some extent after IVIG therapy ( P<0.05). There were no statistical differences in iNOS expression or NO concentration in culture supernatant of G-MDSC among different groups ( P<0.05). (2) Plasma concentrations of IL-6 and G-CSF, and the expression of IL-6Rα, gp130, G-CSFR, pSTAT3 and C/EBPβ increased remarkably during acute phase of KD ( P<0.05). The expression of IRF-8 at transcription level in patients with acute KD was found to be lower than that of healthy controls ( P<0.05), and restored significantly after IVIG therapy ( P<0.05). Moreover, the plasma concentrations of IL-6 and G-CSF and the expression of IL-6Rα, gp130, G-CSFR and IRF-8 in the CAL group were higher than those in the NCAL group ( P<0.05), while the expression of pSTAT3 and C/EBPβ was lower in the CAL group ( P<0.05), which were restored by IVIG therapy ( P<0.05). (3) In patients with acute KD, the expression of SOCS1 and SOCS3 at mRNA level and histone acetylation at the promoters of SOCS1 and SOCS3 genes were reduced significantly in comparison with those in healthy controls ( P<0.05) , but were increased remarkably after IVIG treatment( P<0.05). The four indexes were higher in the CAL group than in the NCAL group ( P<0.05). Pearson correlation analysis showed the expression of SOCS1 and SOCS3 was negatively correlated with the protein level of pSTAT3 in G-MDSC of patients with acute KD ( r=-0.46 and -0.32, P<0.05). Conclusions:Changes in the number and function of G-MDSC caused by aberrant histone acetylation at SOCS1 and SOCS3 genes might contribute to the immune dysfunction and vascular damage in patients with KD.

Experimental research progress on immunology of organ transplantation in 2020 / 器官移植

Despite the rapid development of organ transplantation technique, the long-term survival and functional maintenance of transplant organs still depend on the massive use of immunosuppressants.At present, the rejection and infection after organ transplantation remain the major problem facing transplant surgeons and recipients. The basic research in the field of organ transplantation is still steadily advancing to further explore the basic biological principle of rejection and immune tolerance, resolve multiple pathophysiological questions in the process of clinical organ transplantation and provide basic theoretical basis and clinical intervention guidance for wider and more effective application of organ transplantation.In 2020, researchers have achieved significant progresses on a wide range of basic researches of organ transplantation, such as the fundamental principle of immune response, overcoming transplantation rejection and inducing transplantation immune tolerance, etc.In this article, novel attempts and progresses upon inducing transplantation immune tolerance in 2020 were reviewed from two perspectives including inhibition of immune cell function and suppression of immune signaling pathway, and the main development direction of immunology of organ transplantation in the future was prospected.

Research progress on myeloid-derived suppressor cell and transplantation immune tolerance / 器官移植

Myeloid-derived suppressor cell (MDSC) is a type of heterogeneous cell derived from bone marrow, which was first found in tumor. MDSC can inhibit the function of T cell with immunosuppressive effect. In recent years, more and more studies have shown that in the field of organ transplantation, MDSC can also regulate the host's immune function, induce specific immune tolerance, and play a protective role in transplant organs, which is expected to become a new target in clinical treatment of transplant rejection. The biological characteristics of MDSC and the mechanism of immune tolerance induced by MDSC were reviewed in this paper.

Construction and anti-tumor efficacy of a peptide vaccine that targets calcium-binding protein S100A9 / 药学学报

Calcium-binding protein S100A9 is closely related to inflammation and tumor invasion, and is one of the specific markers of myeloid-derived suppressor cells (MDSC). In this study, a recombinant polypeptide vaccine CTB-S100A9 targeting mouse calcium-binding protein S100A9 was constructed by fusion cholera toxin B subunit (CTB) with S100A9 gene. The CTB-S100A9 fusion protein was expressed in E coli. and purified by Ni+ affinity chromatography. Vaccinate the purified recombinant CTB-S100A9 protein supplemented with aluminum hydroxide adjuvant can break the autoimmune tolerance and produce high titer of S100A9 antibody in mice. Moreover, the S100A9 antibody produced by CTB-S100A9 vaccination is more specific and does not cross-react with S100A8. In the mouse 4T1 breast cancer model, CTB-S100A9 vaccination not only has significant tumor prevention effects, but also has significant tumor therapeutic effects. In addition, CTB-S100A9 significantly inhibited lung metastasis in 4T1 mice breast cancer model. Further analysis by flow cytometry showed that CTB-S100A9 vaccination can significantly reduce the tumor induced Treg cells and granulocyte-derived MDSC in 4T1 mice model, and reverse the tumor immunosuppressive environment, thereby promote the anti-tumor efficacy. The animal experiments in this study were carried out under the animal care guidelines approved by the Animal Ethics Committee of the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine. This study shows that CTB-S100A9 is a good recombinant vaccine that targets the tumor immune-suppression environment and has great potential for the future clinical application.

Immunomodulatory effect of myeloid-derived suppressor cell and its impact on tumor therapy / 上海交通大学学报（医学版）

Myeloid-derived suppressor cells (MDSCs) are a group of cells with potent immune suppressive activity which have emerged as an important contributor to tumor progression and genesis. More and more clinical researches have found that accumulation of MDSCs in peripheral blood and tumor tissues could predict dismal outcome for patients with malignancies, which was a potential prognostic tumor marker. In addition, immunosuppression induced by MDSCs could reduce the efficacy of anti-tumor therapies. Therefore, better understanding the mechanism of MDSCs’ immune suppression in tumor microenvironment can provide reference for exploring new immunotherapies.

Dynamic changes of myeloid-derived suppressor cells and regulatory T cells in livers of mice infected with Echinococcus granulosus / 中国血吸虫病防治杂志

Objective To investigate the dynamics changes of the myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells in mice infected with Echinococcus granulosus and explore the possible biological significance. Methods Thirty female BALB/c mice of 6 weeks old were randomly divided into the infection and control groups, of 15 mice in each group. Mice in the infection group were intraperitoneally injected with 2 000 E. granulosus protoscoleces, while those in the control group were injected with the same volume of physiological saline. Mouse liver white blood cells were harvested 3 (early stage), 6 (medium stage) and 12 months (late stage) post-infection, and the proportions of MDSCs, their subpopulations (M-MDSCs and PMN-MDSCs) and Treg cells were assessed by flow cytometry. Results The proportions of MDSCs were (1.61 ± 0.36)%, (5.68 ± 0.69)% and (16.18 ± 0.69)% in mouse liver white blood cells in the infection group 3, 6 and 12 months post-infection with E. granulosus, and (2.19 ± 0.42)%, (0.99 ± 0.07) % and (4.18 ± 0.84)% in the control group, and there were significant differences in the proportion of the MDSCs in mouse liver white blood cells between the infection and control groups 6 and 12 months post-infection (P < 0.01). The proportions of M-MDSCs were (0.69 ± 0.27)%, (5.30 ± 0.72)% and (10.75 ± 0.29)% in mouse liver white blood cells in the infection group 3, 6 and 12 months post-infection, and (0.42 ± 0.24)%, (0.69 ± 0.02)% and (2.12 ± 0.13)% in the control group, and there were significant differences in the proportion of the M-MDSCs in the mouse liver white blood cells between the infection and control groups 6 and 12 months post-infection (P < 0.01). The proportions of PMN-MDSCs were (0.93 ± 0.23)%, (0.32 ± 0.02)% and (5.14 ± 1.03)% in mouse liver white blood cells in the infection group 3, 6 and 12 months post-infection, and (1.77 ± 0.26)%, (0.28 ± 0.05)% and (1.99 ± 0.90)% in the control group, and there were significant differences in the proportion of PMN-MDSCs in mouse liver white blood cells between the infection and control groups 3 and 12 months post-infection (P < 0.05). The proportions of Treg cells were (3.35 ± 0.14)%, (6.24 ± 0.38)% and (3.41 ± 0.07)% in mouse liver white blood cells in the infection group 3, 6 and 12 months post-infection, and (3.48 ± 0.46)%, (3.65 ± 0.45)% and (3.12 ± 0.12)% in the control group, and there were significant differences in the proportion of Treg cells in mouse liver white blood cells between the infection and control groups 6 and 12 months post-infection (P < 0.01). Conclusions The percentages of both MDSCs and Treg cells increase in mouse liver white blood cells 6 and 12 months post-infection with E. granulosus, and a more remarkable increase is seen in the percentage of MDSCs, which is mainly found in M-MDSCs. These findings suggest that M-MDSCs may play a major immunosuppressive role in the medium and late stages of E. granulosus infection in mice.

Dynamic changes of myeloid-derived suppressor cells and regulatory T cells in livers of mice infected with Echinococcus granulosus / 中国血吸虫病防治杂志

Objective To investigate the dynamics changes of the myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells in mice infected with Echinococcus granulosus and explore the possible biological significance. Methods Thirty female BALB/c mice of 6 weeks old were randomly divided into the infection and control groups, of 15 mice in each group. Mice in the infection group were intraperitoneally injected with 2 000 E. granulosus protoscoleces, while those in the control group were injected with the same volume of physiological saline. Mouse liver white blood cells were harvested 3 (early stage), 6 (medium stage) and 12 months (late stage) post-infection, and the proportions of MDSCs, their subpopulations (M-MDSCs and PMN-MDSCs) and Treg cells were assessed by flow cytometry. Results The proportions of MDSCs were (1.61 ± 0.36)%, (5.68 ± 0.69)% and (16.18 ± 0.69)% in mouse liver white blood cells in the infection group 3, 6 and 12 months post-infection with E. granulosus, and (2.19 ± 0.42)%, (0.99 ± 0.07) % and (4.18 ± 0.84)% in the control group, and there were significant differences in the proportion of the MDSCs in mouse liver white blood cells between the infection and control groups 6 and 12 months post-infection (P < 0.01). The proportions of M-MDSCs were (0.69 ± 0.27)%, (5.30 ± 0.72)% and (10.75 ± 0.29)% in mouse liver white blood cells in the infection group 3, 6 and 12 months post-infection, and (0.42 ± 0.24)%, (0.69 ± 0.02)% and (2.12 ± 0.13)% in the control group, and there were significant differences in the proportion of the M-MDSCs in the mouse liver white blood cells between the infection and control groups 6 and 12 months post-infection (P < 0.01). The proportions of PMN-MDSCs were (0.93 ± 0.23)%, (0.32 ± 0.02)% and (5.14 ± 1.03)% in mouse liver white blood cells in the infection group 3, 6 and 12 months post-infection, and (1.77 ± 0.26)%, (0.28 ± 0.05)% and (1.99 ± 0.90)% in the control group, and there were significant differences in the proportion of PMN-MDSCs in mouse liver white blood cells between the infection and control groups 3 and 12 months post-infection (P < 0.05). The proportions of Treg cells were (3.35 ± 0.14)%, (6.24 ± 0.38)% and (3.41 ± 0.07)% in mouse liver white blood cells in the infection group 3, 6 and 12 months post-infection, and (3.48 ± 0.46)%, (3.65 ± 0.45)% and (3.12 ± 0.12)% in the control group, and there were significant differences in the proportion of Treg cells in mouse liver white blood cells between the infection and control groups 6 and 12 months post-infection (P < 0.01). Conclusions The percentages of both MDSCs and Treg cells increase in mouse liver white blood cells 6 and 12 months post-infection with E. granulosus, and a more remarkable increase is seen in the percentage of MDSCs, which is mainly found in M-MDSCs. These findings suggest that M-MDSCs may play a major immunosuppressive role in the medium and late stages of E. granulosus infection in mice.

Role of tumor-associated myeloid cells in the formation of immune microenvironment in multiple myeloma / 白血病·淋巴瘤

Although great progress has been made in the treatment of multiple myeloma (MM), it is still an incurable malignant plasma cell tumor. In addition to the MM cell itself, the bone marrow microenvironment also plays a critically important role to prompt MM cell's survival, growth, and drug resistance. Bone microenvironment reformed by MM cells could not only help the proliferation of MM cells, but also inhibit the killing of the immune system to MM. A variety of cell components and mechanisms participate in the formation of immune microenvironment, including high-profile tumor associated myeloid cells (TAMC). This paper introduces the mechanisms of TAMC in MM immunosuppressive microenvironment.

Relationship Between Myeloid-derived Immunosuppressive Cells (MDSC) and Dialectical Relationship of TCM with Primary Liver Cancer / 世界科学技术-中医药现代化

Objective: To explore the dialectical relationship between immunosuppressed cell expression and TCM inpatients with liver cancer. Methods: The clinical data of 237 HBV-related primary liver cancer patients were collectedand the differences of MDSC expression and clinical BCLC stage and intrahepatic metastasis were analyzed. Peripheralvenous blood was taken for the detection of MDSC (CD33/CDl4/HLA-DR-/low/CDllb) expression in mononuclear cells, helper T cells (Th1, Th2) and interleukin (IL-12, IL-4) ) detection. Results: There was a significant difference betweenliver stagnation and spleen deficiency syndrome (24.21％) and qi stagnation and blood stasis syndrome (5.54％) (Χ2=11.544, P ＜ 0.05) . The expression of MDSC (21.03％) was higher than that of liver-kidney yin deficiency (5.10％) in advanced hepatocellular carcinoma (＞ 5 cm) (Χ2= 8.223, P ＜ 0.005); the expression of Th2 in liver stagnation and spleendeficiency was higher than that of qi stagnation. There was a significant difference between groups in blood stasis group (t = 10.341, P ＜ 0.05) . The expression of Th2 in wet sputum was higher than that in liver and kidney yin deficiency group.There was significant difference between groups (t = 16.307, P ＜ 0.01) . The IL-4 in liver stagnation and spleendeficiency group (76.57 ± 5.01) was higher than that in qi stagnation and blood stasis group (121.70 ± 6.22); There was asignificant difference between groups (t = 21.414, P ＜ 0.05) . There was a significant difference in IL-4 (375.12 ± 5.31) inthe liver-kidney yin deficiency group compared with the group with wet phlegm (115.46 ± 4.15) (t = 12.455, P ＜ 0.05) .Conclusion: MDSC participates in tumor proliferation, invasion and metastasis by regulating Th2 and IL-4, which isclosely related to the dialectical classification of TCM.

Roles of human leukocyte antigen-G ( HLA-G) in MDSC proliferation, M1/M2 macrophage differ-entiation and tumor immune evasion / 中华微生物学和免疫学杂志

Objective To investigate the roles of human leukocyte antigen-G ( HLA-G) in mye-loid-derived suppressor cell (MDSC) proliferation and M1/M2 macrophage differentiation in C57BL/6-NCI-H446-G tumor-bearing mice for better understanding the mechanisms of HLA-G involved in tumor immune evasion. Methods NCI-H446 ( human small cell lung cancer cells) and NCI-H446-G ( NCI-H446 cells ex-pressing HLA-G) cells were labeled with CFSE at a final concentration of 1μmol/L. CFSE fluorescence lev-els were measured by flow cytometry at different time points. Mouse tumor models were established by subcu-taneous injection of C57BL/6 mice with NCI-H446 and NCI-H446-G cells, respectively. PBS was used to set up negative control group. The mice in each group were sacrificed to collect tissue samples on 5 d, 10 d, 15 d and 20 d after injection. The percentages of splenic CD11b+Gr1+MDSCs, F4/80+CD80+M1 and F4/80+CD206+M2 macrophages were analyzed by flow cytometry. Results Steady expression of HLA-G in NCI-H446-G cells was confirmed by Western blot and flow cytometry. HLA-G enhanced the proliferation of NCI-H446 cells. Tumor size increased dramatically in tumor-bearing mice in the first five days and then de-creased over time. The tumor-bearing mice in the NCI-H446-G group had larger tumor than those in the NCI-H446 group in every time point (P<0. 05) and required longer time to fully reject the tumor. Compared with the PBS and NCI-H446 groups, the percentage of splenic MDSCs in tumor-bearing mice was significantly in-creased in the NCI-H446-G group (P<0. 05). Moreover, the ratio of M1/M2 in NCI-H446-G tumor-bearing mice was much lower than that in the other two groups (P<0. 05). Conclusion This study indicated that HLA-G could increase the percentage of MDSCs and decrease the ratio of M1/M2, which might illustrate the role of HLA-G in tumor immune evasion and its potential clinical significance in cancer immunotherapy.

Effect of myeloid-derived suppressor cells on B cell function in mice bearing breast cancer / 中国肿瘤生物治疗杂志

@# Objective: To investigate the effect of myeloid-derived suppressor cells (MDSCs) from mice bearing breast cancer on the function of normal B cells. Methods:ABABL/c mouse 4T1 breast cancer model was established. The spleen MDSCs of tumor-bearing mouse and normal mouse spleen B cells were sorted by magnetic beads, and the sorted MDSCs and B cells were co-incubated. Flow cytometry was used to test the effect of MDSCs on the expressions of B cell surface molecules, including PD-1, PD-L1, CTLA-4, CCR6, CD62L and MHCⅡ; ELISA assay was used to detect the secretion of IgA, IgM and IgG by B cells; BrdU kit was used to detect B cell proliferation; andAnnexin V/PI staining was used to detect B cell apoptosis. B cells in the co-culture system were again sorted by magnetic beads and were then co-cultured with T cells; BrdU kit was used to detect T cell proliferation, and Annexin V/PI was used to detect T cell apoptosis. Results: Compared with B cell control group, the expression of PD-L1 on B cells in B+MDSC group was increased (P<0.01), while the expressions of PD-1, CTLA-4, CCR6, CD62L and MHC Ⅱ were all decreased (all P<0.01); The IgA, IgM and IgG secreted by B cells were significantly increased (all P<0.01); the proliferation of B cells was increased (P<0.01) and the apoptosis was decreased (P<0.01). Compared with the T cell control group, the proliferation of T cells in the B+MDSC (1:5) +T group was significantly reduced (P<0.01); however, there was no significant difference in T cell apoptosis. Conclusion: MDSCs from breast cancer bearing mice promotes B cell proliferation and inhibits B cell apoptosis, and the MDSC-induced B cells can inhibit T cell proliferation.

Clinical significance of B7-H3, an expression membrane type of myeloid-derived suppressor cell in patients with acute pancreatitis / 中华急诊医学杂志

Objective To explore the clinical significance of B7 family homology factor-3 (B7-H3),an expression membrane type of myeloid-derived suppressor cell (MDSC),in patients with acute pancreatitis (AP).Methods A total of 63 patients with AP initially treated in the Emergency Department at the First Affiliated Hospital of Soochow University from January,2014 to December,2015 were selected.Of them,25 suffered from mild AP (MAP),20 had moderate AP (MSAP) and 18 had severe AP (SAP).Another 20 healthy subjects with matching age and gender served as the control group.All patients with AP conformed to the diagnostic criteria of Guidelines or Diagnosis and Treatment of Acute Pancreatitis set in 2013 in China.Patients with other underlying diseases that might influence the clinical outcomes were excluded,including those with tumors,autoimmune diseases,viral infections,trauma and other disorders.A flowcytometer was used to detect the expression rate of MDSC in peripheral venous blood and the expression of B7-H3 on MDSC membrane.The continuous monitoring was carried out for 24 h,48 h and 72 h in patients with AP.Results Compared with healthy subjects,the MDSC cells in patient groups 24 hours after AP onset increased notably (P ＜0.01) especially the highest increase in the SAP group,followed by the MSAP group and the lowest in the MAP group.There were significant differences in pairwise comparisons (P ＜ 0.05).From successive observation of each group,there was no significant difference in MDSC between the MAP group and the MSAP group 24 hours,48 hours and 72 hours after AP onset.However,MDSC reached its peak 48 hours after AP onset,but it declined 72 hours after AP onset in the SAP group (P ＜ 0.05).B7-H3 expressed significantly 24 hours after AP onset,but there was no expression of B7-H3 in the healthy group.Meanwhile,B7-H3 was expressed most highly in the SAP group,followed by the MSAP group and lowest in the MAP group.There were significant differences in expression of B7-H3 found in pairwise comparisons (P ＜ 0.05).The successive observation showed that there was no significant difference in B7-H3 expression between the MAP group and the MSAP group 24 hours,48 hours and 72 hours after AP onset.However,there was a trend of increase in B7-H3 expression as time prolonged found among 24 hours,48 hours and 72 hours after AP onset in the SAP group (P ＜ 0.05).Conclusions The expressions of MDSC and B7-H3 were high in AP,and there were significant differences in both expressions among MAP,MSAP and SAP groups.These phenomena offer clues in further understanding about the immunological disorders during AP giving better guidelines for clinical practice.

The levels and clinical significance of myeloid-derived suppressor cell in peripheral blood from juvenile idiopathic arthritis / 中华风湿病学杂志

Objective Myeloid-derived suppressor cell (MDSC) have the potential to suppress autoimmune T cell response, while the levels and function of it had not been studied in juvenile idiopathic arthritis (JIA). Therefore, we used flow cytometry to detect MDSC in peripheral blood of JIA and analyzed its correlation with cytokines, providing clinical basis for the generation and function of MDSCs in JIA. Methods A total of 34 patients with JIA were included. The disease activity was evaluated by calculating the 28-joint Disease Activity Score (DAS28)based on clinical information. JIA patients were divided into the active disease group and inactive disease group according to the DAS28 score. Twenty healthy controls were recruited from the Health Care Section of our hospital.The frequency of MDSC in peripheral blood from JIA patients and healthy controls were determinedby flow cytometry; enzyme-linked immunosorbent assay (ELISA) was used to detect plasma Interleukin (IL)-1β, IL-6, IL-10 and IL-17A of JIA patients and healthy controls; RT-quantitative polymerase chain reaction (qPCR) was performed to detect the expression levels of signal transducer and activator of transcription 3 (STAT3),IL-17A gene in patients with JIA and control subjects,and Spearman correlation was used to investigate the association between MDSC and DAS28 score, cytokines;non-parametric test and Spearman test were used for two group comparisons and correlation analysis, respectively.Results The frequency of MDSC [(6.2±4.2)% vs (1.2±1.6)%, Z=-5.258, P<0.01], and the levels of plasma cytokines IL-1β [(175±306) pg/ml vs (66±29) pg/ml, Z=-2.246, P=0.034], IL-6 [(86.6±257.2) pg/ml vs (14.0± 2.6)pg/ml,Z=-3.123,P=0.002),IL-10[(44±36)pg/ml vs(24±6)pg/ml,Z=-2.166,P=0.03],IL-17A[(9.1±17.6) pg/ml vs (2.7±0.4) pg/ml, Z=-3.965, P<0.01] incre-ased significantly in JIA patients compared with healthy control group, while STAT3 had no differences (P>0.05). The frequency of MDSC correlated positively with DAS28 and erythrocyte sedimentation rate(ESR) disease activity (r=0.447, P=0.037; r=0.456, P=0.033), IL-1β (r=0.496, P=0.044), IL-10 (r=0.498, P=0.035); negatively cor-related with the STAT3 mRNA (r=-0.522, P=0.041); but not correlated with the IL-6, IL-17A by Spearman's test. Conclusion We have found that the frequency of MDSC in JIA increases and is associated disease activity, closely associated with inflammatory cytokines. The frequency of MDSC can be used as a clinical indicator to reflect inflammatory activity in JIA, However,the current knowledge of MDSC is incomplete and further experiment is required.

Changes in myeloid-derived suppressor cells (MDSC), Treg and Th17 cells in peripheral blood of patients with cervical human papillomavirus (HPV) infection / 中华微生物学和免疫学杂志

Objective To investigate the changes in myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg) and T helper 17 (Th17) cells in peripheral blood of patients with HPV infection and cervical diseases including ectopic cervical columnar epithelium (CE), cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (CC), and to analyze the roles of MDSC, Treg and Th17 cells in the development of cervical diseases.Methods This study enrolled 120 HPV-positive patients with cervical diseases (18 cases of CE, 50 cases of CIN, 52 cases of CC), 20 HPV-negative patients with cervical diseases (10 cases of CE and 10 cases of CIN) and 20 healthy subjects from March 2011 to December 2016.Changes in MDSC, Treg and Th17 cells in peripheral blood of all patients were detected by flow cytometry.Results Percentages of MDSC, Treg and Th17 cells in peripheral blood of patients who were positive for HPV were significantly higher than those in HPV-negative patients (P<0.05).Besides, percentages of these cells gradually increased with the exacerbation of cervical disease (CE-CINⅠ-CINⅡ-CINⅢ-CC) (P<0.05).Patients who were infected with high-risk HPV had significantly higher percentages of MDSC, Treg and Th17 cells in peripheral blood than those infected with low-risk HPV (P<0.05).Changes of MDSC, Treg and Th17 cells in peripheral blood of HPV-positive patients with cervical cancer were related to International Federation of Gynecology and Obstetrics (FIGO) stage, tumor differentiation, lymph node metastasis and vascular invasion (P<0.05).MDSC, Treg and Th17 cells in peripheral blood of all patients were significantly reduced after treatment (P<0.05).Patients whose status changed from HPV-positive to HPV-negative following treatment also showed significantly decreased MDSC, Treg and Th17 cells in peripheral blood as compared with those who remained HPV-positive (P<0.05).MDSC, Treg and Th17 cells in peripheral blood of HPV-positive patients with cervical diseases were positively correlated (r=0.599, 0.677, 0.648;P<0.05).Conclusion MDSC, Treg and Th17 cells in peripheral blood of patients with HPV infection are associated with the pathological process, severity and clinical pathological features of cervical diseases as well as therapeutic effects.Therefore, they can be used as biomarkers to detect the occurrence and development of HPV-positive cervical diseases.

Changed percentage of myeloid-derived suppressor cells in the peripheral blood of prostate cancer patients and its clinical implication / 中华男科学杂志

<p><b>Objective</b>To investigate the changes in the percentage of myeloid-derived suppressor cells (MDSCs) in the peripheral blood of prostate cancer (PCa) patients and explore the correlation of MDSCs and their subsets with the prognosis of PCa.</p><p><b>METHODS</b>Using flow cytometry, we determined the percentage of MDSCs and the levels of Arg-1, iNOS and PD-L1 in the peripheral blood of 32 PCa patients and 25 healthy controls, detected the distribution of CD14+ Mo-MDSC and CD15+ PMN-MDSC subsets, and analyzed the correlation between the obtained parameters and the prognosis of PCa.</p><p><b>RESULTS</b>Compared with the healthy controls, the PCa patients showed significant increases in the percentage of MDSCs (P<0.01) and levels of Arg-1, iNOS and PD-L1 in the peripheral blood. Statistically significant differences were observed in the distribution of the CD14+ Mo-MDSC and CD15+ PMN-MDSC subsets between the two groups（60.4% vs 72.2%, 29.5% vs 18.8%） (P<0.05). The percentages of MDSCs and Mo-MDSCs were remarkably correlated with the total survival rate of the PCa patients (P=0.025 and 0.017).</p><p><b>CONCLUSIONS</b>The percentages of MDSCs and CD14+ Mo-MDSCs in the peripheral blood were correlated with the prognosis of PCa, which may provide a target or some evidence for the clinical treatment of PCa.</p>