RIP3 Blockade Drives Myeloid-Derived Suppressor Cell-Mediated Immune Tolerance in Immune-Mediated Hepatitis

2020 ◽  
Author(s):  
Man Liu ◽  
Hongxia Zhang ◽  
Lu Zhang ◽  
Xin Liu ◽  
Simin Zhou ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Suppressor Cell ◽  
Myeloid Derived Suppressor Cell ◽  
Immune Mediated

scholarly journals RIP3 blockade prevents immune-mediated hepatitis through a myeloid-derived suppressor cell dependent mechanism

2022 ◽  
Vol 18 (1) ◽  
pp. 199-213
Author(s):  
Man Liu ◽  
Hongxia Zhang ◽  
Lu Zhang ◽  
Xin Liu ◽  
Simin Zhou ◽  
...  
Keyword(s):  
Suppressor Cell ◽  
Myeloid Derived Suppressor Cell ◽  
Immune Mediated ◽  
Dependent Mechanism

scholarly journals Low-dose decitabine modulates myeloid-derived suppressor cell function and restores immune tolerance in immune thrombocytopenia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2089-2089
Author(s):  
Xiaofei Ni ◽  
Lingjun Wang ◽  
Tianshu Yu ◽  
Haoyi Wang ◽  
Yu Hou ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Immune Thrombocytopenia ◽  
Low Dose ◽  
Cell Function ◽  
Suppressor Cell ◽  
Healthy Controls ◽  
Suppressive Activity ◽  
Wild Type ◽  
Myeloid Derived Suppressor Cell ◽  
Healthy Control

Abstract Low-dose decitabine modulates myeloid-derived suppressor cell function and restores immune tolerance in immune thrombocytopenia Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized with increased risk of bleeding. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. Metabolic changes within MDSCs elucidate a direct influence on immunologic consequences of their suppressive activity. Liver kinase B1 (LKB1) is a tumor suppressor gene of STK11/LKB1 coding serine/Sue, and LKB1 signaling pathway plays an important role as a "bridge" between metabolic balance and functional homeostasis of immune cells. Our previous studies demonstrated that low dose decitabine, a hypomethylating agent, significantly increased the number of mature polyploidy megakaryocytes and exhibited long-term clinical efficacy. Besides, it also increased the production of Treg and enhanced their immunosuppressive function in ITP. However, whether decitabine could regulate the metabolic and suppressive activity of MDSCs in ITP is unknown. The percentage of MDSCs in peripheral blood mononuclear cells (PBMCs) was determined by flow cytometry, which was shown to be significantly lower in ITP compared with that in healthy controls. We then investigated the effect of low-dose decitabine in patients with active ITP, where decitabine induced a significant expansion of MDSCs in line with an impressive platelet response. In the in vitro experiments, MDSCs were isolated from PBMCs of ITP patients or healthy controls and cultured with different concentrations of decitabine (0/10nM/50nM/100 nM/1uM/10μM) for 7 days. A concentration gradient from 50nM to 1uM stimulated MDSCs amplification in a dose-dependent manner, and we chose an optimal concentration of 100 nM. Moreover, we found the mRNA expression level of LKB1, AMPKα1, AMPKα2, AMPKβ1, AMPKβ2, AMPKγ1, and AMPKγ2 was significantly lower in ITP patients than that in healthy control subjects. After incubation with decitabine (100nM), the relative expression of the above molecules were significantly increased compared to untreated levels. We also analyzed oxygen consumption rate (OCR) and key parameters of mitochondrial function within MDSCs. Overall, the OCR curve of ITP patients was lower than that of the healthy control subjects, and the OCR curve of ITP patients significantly improved after treatment with decitabine. We sorted the cultured MDSCs and co-cultured them with CFSE-labeled CD4 +CD25 - T cells to evaluate the suppressive activity of MDSCs. Results indicated that the inhibitory function of decitabine-modulated MDSCs was corrected in line with metabolic rewriting. We further established the ITP murine model by transferring splenocytes of C57BL/6 CD61 knockout mice, immunized against platelets from wild-type syngeneic C57BL/6 mice, into severe combined immune deficient (SCID) mice. MDSCs were sorted from the bone marrow of wild-type mice and incubated with PBS or decitabine, respectively. SCID mice were divided into three groups and received the same numbers of splenocyte transfer, two groups were given additional transfer of PBS-treated or decitabine-treated MDSCs. Our data showed that the decitaine-treated MDSCs group had significantly higher platelet counts compared with control group and PBS-treated MDSCs group. In summary, our findings suggest that the immune function and metabolic characteristics of MDSCs in ITP patients are impaired. These data shed new light on the molecular mechanism of decitabine action by regulating immune function and aerobic metabolism via LKB1, which supervises the immunosuppressive functions of MDSCs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Myeloid-derived suppressor cell (MDSC) key genes analysis in rat anti-CD28-induced immune tolerance kidney transplantation

2021 ◽  
Vol 10 (1) ◽  
pp. 204-214
Author(s):  
Tianying Yang ◽  
Jiawei Li ◽  
Yichen Jia ◽  
Chunchen Yang ◽  
Ruirui Sang ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Immune Tolerance ◽  
Suppressor Cell ◽  
Myeloid Derived Suppressor Cell ◽  
Key Genes

scholarly journals Targeting MDSC for Immune-Checkpoint Blockade in Cancer Immunotherapy: Current Progress and New Prospects

2021 ◽  
Vol 15 ◽  
pp. 117955492110355
Author(s):  
Tianhang Li ◽  
Tianyao Liu ◽  
Wenjie Zhu ◽  
Shangxun Xie ◽  
Zihan Zhao ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Escape ◽  
Suppressor Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Great Promise ◽  
Therapy Process ◽  
Myeloid Derived Suppressor Cell ◽  
Anti Cancer ◽  
Immune Suppressor

Immune-checkpoint blockade (ICB) demonstrated inspiring effect and great promise in anti-cancer therapy. However, many obstacles, such as drug resistance and difficulty in patient selection, limited the efficacy of ICB therapy and awaited to be overcome. By timely identification and intervention of the key immune-suppressive promotors in the tumor microenvironment (TME), we may better understand the mechanisms of cancer immune-escape and use novel strategies to enhance the therapeutic effect of ICB. Myeloid-derived suppressor cell (MDSC) is recognized as a major immune suppressor in the TME. In this review, we summarized the roles MDSC played in the cancer context, focusing on its negative biologic functions in ICB therapy, discussed the strategies targeted on MDSC to optimize the diagnosis and therapy process of ICB and improve the efficacy of ICB therapy against malignancies.

scholarly journals Mast Cells Boost Myeloid-Derived Suppressor Cell Activity and Contribute to the Development of Tumor-Favoring Microenvironment

2014 ◽  
Vol 3 (1) ◽  
pp. 85-95 ◽  
Author(s):  
Luca Danelli ◽  
Barbara Frossi ◽  
Giorgia Gri ◽  
Francesca Mion ◽  
Carla Guarnotta ◽  
...  
Keyword(s):  
Mast Cells ◽  
Cell Activity ◽  
Suppressor Cell ◽  
Myeloid Derived Suppressor Cell
Sign in / Sign up

Export Citation Format

Share Document