免疫系统包括一系列的免疫细胞和激活免疫反应的调节因子，正常的免疫系统可以保护机体免受各种病原体的侵害。免疫系统失调会导致各种各样的免疫性疾病，例如过敏，自身免疫性疾病和肿瘤。子宮内膜异位症是妇科常见慢性疾病之一，其特点为子宮内膜腺体和间质种植在子宮体以外部位。倒流的子宮内膜组织成功逃逸免疫系统的监控是成功种植的必要条件，然而其病理机制尚未研究清楚。 / 本研究探索了子宮内膜异位症小鼠模型24小时内腹腔免疫细胞的变化。我们发现大部分免疫细胞在子宮内膜组织移植24小时内显著降低，然而骨髓源性抑制细胞（MDSC）的比例大幅度增高。子宮内膜移植后6小时内已经有大量MDSC到达腹腔，并在子宮内膜粘附增生阶段都维持在高水平。子宮内膜异位诱导的腹腔MDSC包括两个细胞亚型，CD11b⁺Ly-6G⁺Ly-6C{U+02E1}{U+1D52}{U+02B7}粒细胞型MDSC (G-MDSC) 和CD11b⁺Ly-6G-Ly-6C{U+02B0}{U+2071}{U+1D4D}{U+02B0}单核细胞型MDSC (-MDSC)，二者都能够显著抑制T细胞增生，表明MDSC在早期子宮内膜异位症发展过程中介导了免疫抑制的发生。用Gr-1抗体去除子宮内膜异位症小鼠模型中的MDSC后，异位病灶的生长相比对照组受到显著抑制。同时，粒细胞集落刺激因子（G-CSF）在内膜组织移植后6小时内也明显增高，体内补充G-CSF会引起正常小鼠骨髓和周围血中MDSC的比例增高，这表明G-CSF可以诱导MDSC在骨髓中增生，并且在周围血中聚集。然而，G-CSF不能引起腹腔中MDSC增多，提示还有其他的因子参与了MDSC的趋化反应。 / 本研究表明MDSC在子宮内膜异位症发生发展过程中很可能通过类似于抑制肿瘤免疫反应的免疫抑制作用，而推动子宮内膜免疫逃逸过程，最终导致异位子宮内膜存活并生长。因此，MDSC可能成为研发子宮内膜异位症新治疗方案的靶点。 / Normal immune system keeps human bodies remain intact and unharmed in the midst of a vast universe of pathogens. The immune system includes a series of cells and molecules which worked together to initiate immune response. The dysfunction of immune cells or modulators results in various diseases, such as allergic diseases, autoimmune diseases and tumors. Endometriosis is a chronic gyneacological disorder characterized by the implantation of endometrial glands and stroma outside the uterus. The successful immune escape of retrograded endometrial cell from immune surveillance is one of the key steps in the development of endometriosis. The underlying mechanism is still unknown. / In this study, we observed the profiles of peritoneal immune cells and cytokines within 24 hours (h) after the transplantation of endometrial fragments in peritoneal cavity in mice. Most of the peritoneal immune cells decreased after the transplantation, except myeloid derived suppressor cells (MDSC) were significantly increased within 24 h. MDSC was increased in the peritoneal cavity as early as 6 h and maintained at high level when the endometrial fragments attached and proliferated in the following days. The increased MDSC have CD11b⁺Ly-6G⁺Ly-6C{U+02E1}{U+1D52}{U+02B7} granulocytic MDSC (G-MDSC) and CD11b⁺Ly-6G-Ly-6C{U+02B0}{U+2071}{U+1D4D}{U+02B0} monocytic MDSC (M-MDSC) phenotypes. Isolated peritoneal MDSC significantly suppressed T cell proliferation and activated arginase activity, suggesting the immunosuppression of MDSC during early development of endometriosis. Depletion of MDSC by Gr-1 antibody treatment significantly reduced the growth and development of endometriosis. Concurrently, granulocyte colony stimulating factor (G-CSF) was significantly increased as early as 6 h after transplantation. Supplementation of G-CSF in control mice increased MDSC percentage in bone marrow and peripheral blood, but not in peritoneal cavity. This suggests that G-CSF is responsible to induce the proliferation of MDSC in bone marrow and accumulation of MDSC in peripheral blood, but not recruitment into peritoneal cavity. Additional cytokines or chemokines may involve the mobilization of MDSC from peripheral blood to peritoneal cavity. / Our study suggested that MDSC may play an essential role in the immune escape and promote endometrial survival during early development of endometriosis, probably through the similar immunosuppression mechanisms as in cancer. MDSC may be a novel target to develop highly effective therapeutics for treatment of endometriosis. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhang, Tao. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 102-128). / Abstracts also in Chinese. / Acknowledgements --- p.i / Publications --- p.iii / Academic Awards --- p.iii / List of tables and figures --- p.ix / List of abbreviations --- p.ix / Abstract --- p.xv / Chapter Chapter 1 --- Endometriosis --- p.1 / Chapter 1.1 --- Epidemiology --- p.1 / Chapter 1.1.1 --- Prevalence --- p.1 / Chapter 1.1.2 --- Risk factors --- p.2 / Chapter 1.1.2.1 --- Menstrual and reproductive factors --- p.2 / Chapter 1.1.2.2 --- Genetics --- p.3 / Chapter 1.1.2.3 --- Physical and habitual factors --- p.6 / Chapter 1.1.2.4 --- Environmental toxins --- p.6 / Chapter 1.1.2.5 --- Immune comorbidity --- p.7 / Chapter 1.2 --- Pathogenesis --- p.8 / Chapter 1.2.1 --- Retrograde menstruation --- p.8 / Chapter 1.2.2 --- Lymphatic or vascular spread --- p.9 / Chapter 1.2.3 --- Coelomic metaplasia and induction theory --- p.10 / Chapter 1.3 --- Pathophysiology --- p.11 / Chapter 1.3.1 --- Dysfunction of immune system --- p.11 / Chapter 1.3.2 --- Attachment and invasion --- p.12 / Chapter 1.3.3 --- Angiogenesis --- p.12 / Chapter 1.3.4 --- Oxidative stress --- p.13 / Chapter 1.4 --- Symptoms --- p.13 / Chapter 1.4.1 --- Pelvic pain --- p.14 / Chapter 1.4.2 --- Dysmenorrhea --- p.15 / Chapter 1.4.3 --- Dyspareunia --- p.15 / Chapter 1.4.4 --- Infertility --- p.16 / Chapter 1.5 --- Diagnosis --- p.16 / Chapter 1.5.1 --- Laparoscopy --- p.17 / Chapter 1.5.2 --- Laboratory tests --- p.17 / Chapter 1.5.3 --- Imaging --- p.18 / Chapter 1.5.4 --- Therapeutic diagnosis --- p.19 / Chapter 1.6 --- Treatment --- p.19 / Chapter 1.6.1 --- Hormonal therapy --- p.19 / Chapter 1.6.1.1 --- Combined oral contraceptives --- p.20 / Chapter 1.6.1.2 --- Progestogens --- p.20 / Chapter 1.6.1.3 --- Danazol --- p.21 / Chapter 1.6.1.4 --- GnRH Agonists --- p.22 / Chapter 1.6.1.5 --- Gestrinone --- p.23 / Chapter 1.6.2 --- Surgical treatment --- p.23 / Chapter 1.6.2.1 --- Conservative surgery --- p.24 / Chapter 1.6.2.2 --- Definitive surgery --- p.24 / Chapter 1.6.3 --- Treatment of endometriosis-related infertility --- p.25 / Chapter 1.6.4 --- New potential therapies --- p.25 / Chapter 1.6.4.1 --- Angiogenesis inhibitors --- p.26 / Chapter 1.6.4.2 --- Antioxidant therapy --- p.26 / Chapter 1.6.4.3 --- Immunomodulatory therapy --- p.27 / Chapter 1.6.4.3.1 --- Pentoxifylline --- p.27 / Chapter 1.6.4.3.2 --- TNF-α inhibitor --- p.28 / Chapter 1.6.4.3.3 --- Loxoribine --- p.28 / Chapter 1.6.4.4 --- Others --- p.29 / Chapter 1.7 --- Summary --- p.29 / Chapter Chapter 2 --- Immunology of Endometriosis --- p.30 / Chapter 2.1 --- Cell-mediated immunity --- p.30 / Chapter 2.1.1 --- Monocytes/Macrophages --- p.31 / Chapter 2.1.2 --- Dendritic cells --- p.32 / Chapter 2.1.3 --- T lymphocyte --- p.34 / Chapter 2.1.4 --- Natural killer cells --- p.34 / Chapter 2.1.5 --- T regulatory cells --- p.35 / Chapter 2.2 --- Humoral immunity --- p.37 / Chapter 2.3 --- Cytokines and growth factors --- p.39 / Chapter 2.3.1 --- Interleukin-1 --- p.39 / Chapter 2.3.2 --- Interleukin-6 --- p.40 / Chapter 2.3.3 --- Interleukin-8 --- p.41 / Chapter 2.3.4 --- Interleukin-12 --- p.42 / Chapter 2.3.5 --- Monocyte chemotactic protein-1 --- p.43 / Chapter 2.3.6 --- RANTES --- p.43 / Chapter 2.3.7 --- Tumor necrosis factor-α --- p.44 / Chapter 2.3.8 --- Vascular endothelial growth factor --- p.45 / Chapter 2.3.9 --- Growth factors --- p.46 / Chapter 2.3.9.1 --- Insulin-like growth factor --- p.46 / Chapter 2.3.9.2 --- Transforming growth factor beta --- p.46 / Chapter 2.3.9.3 --- Platelet derived growth factor --- p.46 / Chapter 2.3.9.4 --- Macrophage-colony stimulating factor --- p.47 / Chapter 2.3.9.5 --- Hepatocyte growth factor --- p.47 / Chapter 2.4 --- Molecular modulations in immune response --- p.47 / Chapter 2.4.1 --- NF-κB Signaling pathway --- p.47 / Chapter 2.4.2 --- NF-κB activation in endometriosis --- p.48 / Chapter 2.4.3 --- NF-κB activation in endometriosis associated peritoneal immune response --- p.50 / Chapter 2.5 --- The relationship between estrogen and immune response --- p.51 / Chapter 2.5.1 --- Effect of estrogen on immune cells and cytokines --- p.51 / Chapter 2.5.2 --- Effect of hormone treatment on immune response --- p.52 / Chapter 2.6 --- Summary --- p.53 / Chapter Chapter 3 --- Study Hypothesis and Objectives --- p.55 / Chapter 3.1 --- Hypothesis and aims --- p.56 / Chapter 3.2 --- Objectives --- p.56 / Chapter Chapter 4 --- Methodology --- p.57 / Chapter 4.1 --- Experimental design --- p.57 / Chapter 4.2 --- Cell-mediated immunity --- p.58 / Chapter 4.2.1 --- Experimental endometriosis in vivo --- p.58 / Chapter 4.2.2 --- Collection of peritoneal fluid, peritoneal cells and endometrial fragments --- p.59 / Chapter 4.2.3 --- Quantification of peritoneal immune cells --- p.59 / Chapter 4.3 --- MDSC functional analysis --- p.60 / Chapter 4.3.1 --- T cell suppression --- p.60 / Chapter 4.3.1.1 --- Collection and sorting of MDSC and T cells --- p.60 / Chapter 4.3.1.2 --- T cell proliferation assay --- p.61 / Chapter 4.3.2 --- Arginase production of MDSC --- p.62 / Chapter 4.3.2.1 --- Isolation of peritoneal G-MDSC and M-MDSC --- p.62 / Chapter 4.3.2.2 --- Arginase assay --- p.63 / Chapter 4.3.3 --- WrightGiemsa staining --- p.64 / Chapter 4.4 --- Kinetics of G-MDSC and M-MDSC --- p.64 / Chapter 4.4.1 --- Collection of peripheral mononuclear cells --- p.64 / Chapter 4.4.2 --- Collection of bone marrow cells --- p.65 / Chapter 4.5 --- MDSC depletion --- p.65 / Chapter 4.5.1 --- Interventions --- p.65 / Chapter 4.5.2 --- Sample collection --- p.66 / Chapter 4.5.3 --- BrdU staining --- p.66 / Chapter 4.6 --- Peritoneal cytokines and chemokines profile --- p.66 / Chapter 4.6.1 --- Cytokines antibody array --- p.66 / Chapter 4.6.2 --- Chemokines antibody array --- p.67 / Chapter 4.6.3 --- Data analysis of array --- p.68 / Chapter 4.6.4 --- ELISA validation --- p.69 / Chapter 4.6.5 --- Histology and immunohistochemistry --- p.69 / Chapter 4.6.5.1 --- Histology --- p.69 / Chapter 4.6.5.2 --- Immunohistochemistry --- p.70 / Chapter 4.7 --- MDSC proliferation and mobilization --- p.71 / Chapter 4.8 --- Statistics --- p.71 / Chapter Chapter 5 --- Results --- p.72 / Chapter 5.1 --- Histology of endometrial fragment --- p.72 / Chapter 5.2 --- Immune cell profiles --- p.72 / Chapter 5.3 --- Identification of MDSC --- p.73 / Chapter 5.3.1 --- T cell proliferation assay --- p.73 / Chapter 5.3.2 --- Arginase production --- p.74 / Chapter 5.3.3 --- Wright-Giemsa staining --- p.75 / Chapter 5.4 --- Kinetics of G-MDSC and M-MDSC --- p.75 / Chapter 5.5 --- MDSC depletion --- p.76 / Chapter 5.5.1 --- Gr-1 antibody depletion --- p.76 / Chapter 5.5.2 --- Size and weight of endometriotic lesions --- p.76 / Chapter 5.5.3 --- Growth and development of endometriotic lesions --- p.77 / Chapter 5.5.4 --- T cells and macrophages --- p.77 / Chapter 5.6 --- Cytokines and chemokines profiles --- p.78 / Chapter 5.6.1 --- Cytokine and chemokine profiles --- p.78 / Chapter 5.6.2 --- ELISA validation --- p.79 / Chapter 5.6.3 --- Cytokines expression in endometriotic lesions --- p.79 / Chapter 5.7 --- Proliferation and mobilization of MDSC by cytokine --- p.80 / Chapter Chapter 6 --- Discussion --- p.81 / Chapter 6.1 --- MDSC in early endometriosis --- p.81 / Chapter 6.1.1 --- Identification of MDSC --- p.81 / Chapter 6.1.1.1 --- Terminology of MDSC --- p.81 / Chapter 6.1.1.2 --- Subsets of MDSC --- p.81 / Chapter 6.1.1.3 --- Characteristics of MDSC --- p.82 / Chapter 6.1.2 --- MDSC in cancer --- p.83 / Chapter 6.1.2.1 --- Expansion and accumulation of MDSC in cancer --- p.83 / Chapter 6.1.2.2 --- Suppressive mechanisms of MDSC in cancer --- p.84 / Chapter 6.1.2.3 --- Suppressive mechanisms of MDSC subsets --- p.89 / Chapter 6.1.3 --- MDSC in inflammation --- p.90 / Chapter 6.1.4 --- MDSC in endometriosis --- p.90 / Chapter 6.2 --- Other immune cells in early endometriosis --- p.92 / Chapter 6.3 --- Cytokines and chemokines in early endometriosis --- p.93 / Chapter 6.4 --- Potentials of the study --- p.94 / Chapter 6.4.1 --- Potentials for new therapy --- p.95 / Chapter 6.4.1.1 --- Facilitating differentiation of MDSC --- p.95 / Chapter 6.4.1.2 --- Inhibiting MDSC proliferation --- p.96 / Chapter 6.4.1.3 --- Eliminating MDSC --- p.97 / Chapter 6.4.1.4 --- Blockade of MDSC suppressive function --- p.97 / Chapter 6.4.2 --- Potentials for new biomarkers --- p.97 / Chapter 6.5 --- Limitations of the study --- p.98 / Chapter 6.5.1 --- Lack of human study --- p.98 / Chapter 6.5.2 --- Lack of stable cell line --- p.98 / Chapter 6.5.3 --- Unknown mechanisms of MDSC in endometriosis --- p.99 / Chapter 6.5.4 --- Signaling pathway --- p.99 / Chapter Chapter 7 --- Conclusion and future plan --- p.100 / Reference --- p.102 / Chapter Appendices: --- Tables & Figures --- p.128
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_328713 |
| Date | January 2013 |
| Contributors | Zhang, Tao, Chinese University of Hong Kong Graduate School. Division of Obstetrics and Gynaecology. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, bibliography |
| Format | electronic resource, electronic resource, remote, 1 online resource (xviii, 175 leaves) : ill. (some col.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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