髓系抑制细胞、Th17细胞在哮喘患儿外周血中的表达

目的 分析髓系抑制细胞(MDSCs)及Th17细胞在哮喘患儿外周血中的表达情况和临床意义.方法 选取自贡市第一人民医院儿科2013年6月至2015年8月收治的120例哮喘患儿作为观察组,另外选择87例健康儿童作为对照组.应用流式细胞术检测MDSCs、Th17细胞在哮喘患儿外周血中的表达情况.结果 和对照组相比,观察组MDSCs占有核细胞的百分比和Th17细胞占单个核细胞的百分比都显著升高(Hc值分别为56.14、45.98,均P<0.05),差异具有统计学意义.结论 从MDSCs、Th17细胞在哮喘患儿外周血中的表达情况来看,它们可能参与了婴幼儿哮喘的发生与发展过程.     

Increased Galectin-9 expression,a prognostic biomarker of aGVHD,regulates the immune response through the Galectin-9 induced MDSC pathway after allogeneic hematopoietic stem cell transplantation

Galectin-9 (Gal-9) is a β-galactoside-binding soluble lectin family member that exerts its primary biological functions via specific glycoconjugate interactions. Gal-9 expression is closely related to tumor occurrence, development, metastasis and prognosis. In transplant immunology, a high level of Gal-9 expression has been shown to markedly reduce the severity of acute graft rejection and effectively prolong survival time in organ and bone marrow transplantation (BMT) models. The main mechanism of Gal-9-mediated immunoregulation involves the Tim-3/Gal-9 axis in T cells. However, myeloid-derived suppressor cell (MDSC) accumulation in transgenic mice with persistently high Gal-9 expression was observed in a model of lung inflammation, indicating that a potential immunosuppressive mechanism distinct from the Gal-9/Tim-3 axis might exist. In the present study, increased Gal-9 expression and MDSC frequencies before acute graft-versus-host disease (aGVHD) onset were observed in patients who developed aGVHD. Patients with higher Gal-9 expression (≥14.8417 ng/ml) exhibited reduced overall survival and increased cumulative incidences of GVHD at +100 day. We considered the elevated Gal-9 expression before aGVHD onset a secondary inflammatory response. This increase might be part of a negative feedback pathway corresponding to aGVHD pathogenesis. Additionally, a high Gal-9 concentration induced MDSC proliferation in vivo and in vitro. Gal-9-induced MDSCs (G9-MDSCs) suppressed T cell proliferation and activation. An infusion of G9-MDSCs into a graft contributed to the successful control of severe aGVHD and long-term survival in an allogeneic (allo)-BMT mouse model. Thus, we speculated that increased Gal-9 expression after allo-hematopoietic stem cell transplantation is a potential prognostic biomarker of aGVHD. The Gal-9-associated immunosuppressive effects on aGVHD development might occurr through G9-MDSCs and were independent of the Gal-9/Tim-3 axis.     

乳腺癌中MDSCs的扩增和募集及相关临床应用

乳腺癌是女性最常见的恶性肿瘤之一,其转移显著提高了患者的死亡率。肿瘤微环境中多种因素发挥了免疫抑制作用并促进乳腺癌的转移,其中,髓源性抑制细胞（myeloid-derived suppressor cells,MDSCs）是骨髓祖细胞和活化的髓样细胞的异质群体,被认为是肿瘤微环境中发挥免疫抑制作用的重要成分。乳腺癌可以通过多种途径对MDSCs的扩增或募集产生积极影响。作者综述了近年来发现的乳腺癌影响MDSCs扩增或募集的机制,以及这些过程中潜在的治疗靶点。     

Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy

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Role of CD11b+Gr-1+ myeloid cells in AGEs-induced myocardial injury in a mice model of acute myocardial infarction

Aims: Polymorph neutrophils are the predominant inflammatory cells and play a crucial role on the pathogenesis of myocardial injury at the early stage of acute myocardial infarction (AMI). However, the precursors and the differentiation of neutrophils are not fully understood. Here we explored the role of CD11b⁺Gr-1⁺ myeloid-derived suppressor cells (MDSCs) on myocardial injury in the absence and presence of advanced glycation end-products (AGEs) in a mice model of AMI. Methods and Results: Male C57BL/6J mice were selected. Fluorescent actived cell sortor (FACS) data demonstrated significantly increased CD11b⁺Gr-1⁺ MDSCs both in peripheral blood circulation and in the ischemic myocardium at 24 hours post AMI. Quantitative-real-time PCR results also revealed significantly upregulated CD11b and Ly6G mRNA expression in the ischemic myocardium. AGEs treatment further aggravated these changes in AMI mice but not in sham mice. Moreover, AGEs treatment also significantly increased infarction size and enhanced cardiomyocyte apoptosis. The mRNA expression of pro-inflammatory cytokine IL-6 and iNOS2 was also significantly increased in AMI + AGEs group compared to AMI group. Conclusion: These data suggest enhanced infiltration of MDSCs by AGEs contributes to aggravated myocardial injury in AMI mice, which might be one of the mechanisms responsible for severer myocardial injury in AMI patients complicating diabetes.     

Phenotypically resembling myeloid derived suppressor cells are increased in children with HIV and exposed/infected with Mycobacterium tuberculosis

Increased disease susceptibility during early life has been linked to immune immaturity, regulatory T‐cell/TH2 immune biasing and hyporesponsiveness. The contribution of myeloid derived suppressor cells (MDSCs) remains uninvestigated. Here, we assessed peripheral MDSC in HIV‐infected and ‐uninfected children with tuberculosis (TB) disease before, during and after TB treatment, along with matched household contacts (HHCs), HIV‐exposed, ‐infected and ‐uninfected children without recent TB exposure. Serum analytes and enzymes associated with MDSC accumulation/activation/function were measured by colorimetric‐ and fluorescence arrays. Peripheral frequencies of cells phenotypically resembling MDSCs were significantly increased in HIV‐exposed uninfected (HEU) and M.tb‐infected children, but peaked in children with TB disease and remained high following treatment. MDSC in HIV‐infected (HI) children were similar to unexposed uninfected controls; however, HAART‐mediated MDSC restoration to control levels could not be disregarded. Increased MDSC frequencies in HHC coincided with enhanced indoleamine‐pyrrole‐2,3‐dioxygenase (IDO), whereas increased MDSC in TB cases were linked to heightened IDO and arginase‐1. Increased MDSC were paralleled by reduced plasma IP‐10 and thrombospondin‐2 levels in HEU and significantly increased plasma IL‐6 in HI HHC. Current investigations into MDSC‐targeted treatment strategies, together with functional analyses of MDSCs, could endorse these cells as novel innate immune regulatory mechanism of infant HIV/TB susceptibility.     

IL-1RT1 signaling antagonizes IL-11 induced STAT3 dependent cardiac and antral stomach tumor development through myeloid cell enrichment

IL-1 is key driver of gastric tumorigenesis and is a downstream target of IL-11 signaling. Recently, IL-1 cytokines, particularly IL-1β, have been flagged as therapeutic targets for gastric cancer treatment. Here, we assess the requirement for IL-1 signaling in gastric tumorigenesis. gp130^757FF xIL-1RT1^−/− mice were generated to determine the pathological consequence of ablated IL-1 signaling in the IL-11 dependent gp130^757FF mouse model of gastric tumorigenesis. Gastric lesions in gp130^757FF xIL-1RT1^−/− mice were increased in incidence and size compared to gp130^757FF mice. Proximal gastric lesions originated from the cardiac region and were associated with elevated STAT3 activation, loss of specialized gastric cells and a modulated immune response including increased expression of TNF-α and MDSC associated genes. Administration of IL-11 to IL-1RT1^−/− mice showed similar changes to gp130^757FF xIL-1RT1^−/− mice. Spleens from IL-11 treated wildtype mice showed an enrichment of MDSC and gp130^757FF xIL-1RT1^−/− mice had increased MDSCs in the stomach compared to gp130^757FF mice. Furthermore, crossing TNF-α^−/− to gp130^757FF mice resulted in reduced lesion size. We conclude that IL-1 signaling antagonizes IL-11/STAT3 mediated pathology and the genetic deletion of IL-1RT1 results in increased tumor burden. We provide evidence that a likely mechanism is due to IL-11/STAT3 dependent enrichment of MDSCs.     

Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses

CD11b(+) Gr-1(+) immature myeloid cells (ImCs), which are abnormally increased in tumor-bearing mice, were classified into three different subsets according to their phenotypic and morphological characteristics: Gr-1(low) F4/80(+) macrophages (MΦ-ImCs), Gr-1(mid) stab neutrophils (Neut(stab)-ImCs), and Gr-1(high) segmented neutrophils (Neut(seg)-ImCs). In the spleen, only MΦ-ImCs but not Neut(stab)-ImCs and Neut(seg)-ImCs exhibited a significant immunosuppressive activity in MLR. In contrast, tumor-infiltrating leukocytes (TILs) contained only two ImC subsets, MΦ-ImCs and Neut(seg)-ImC, both of which exhibited stronger inhibitory activity against T cells compared with spleen-MΦ-ImCs. Thus, we concluded that tumor-infiltrating MΦ-ImCs and Neut(seg)-ImCs were fully differentiated myeloid-derived suppressor cells (MDSCs) with stronger T-cell inhibitory activity. Indeed, spleen MΦ-ImCs were converted into stronger MΦ-MDSCs by tumor-derived factor (TDF). Moreover, both spleen Neut(stab)-ImCs and Neut(seg)-ImCs differentiated into Neut(seg)-MDSCs with suppressive activity after culture with TDF. We first demonstrated that administration of anti-IL-6R mAb could downregulate the accumulation of MΦ-MDSCs and Neut(seg)-MDSCs in tumor-bearing mice. The elimination of those MDSCs caused subsequent enhancement of antitumor T-cell responses, including IFN-γ-production. The therapeutic effect of anti-IL-6R mAb was further enhanced by combination with gemcitabine (GEM). Thus, we propose that anti-IL-6R mAb could become a novel tool for the downmodulation of MDSCs to enhance antitumor T-cell responses in tumor-bearing hosts.