论白介素-10在抗肿瘤免疫中的作用

发布时间：2018-01-01 06:08

本文关键词：论白介素-10在抗肿瘤免疫中的作用　出处：《中国人民解放军军医进修学院》2010年博士论文　论文类型：学位论文

【摘要】： 基于对携带IL-10报告基因小鼠的研究表明,CD8+T淋巴细胞与髓系细胞是IL-10的主要来源。然而,人们对CD8+T淋巴细胞与髓系细胞产生的IL-10在肿瘤免疫中的作用的了解尚少。我们应用一系列转基因及基因敲除小鼠模型对以下三方面进行研究：1.IL-10缺陷对CTL功能的影响；2.髓系细胞产生IL-10在肿瘤免疫中的作用；3.IL-10对肿瘤微环境形成的影响。我们将浆细胞瘤J558细胞接种于IL-10-/-BALB/c小鼠与野生型BALB/c小鼠体内,发现J558肿瘤细胞在IL-10-／-小鼠体内生长速度明显快于野生型小鼠。而同样的J558肿瘤细胞接种在体内缺乏T与B淋巴细胞的IL-10-/-RAG-2-/-与IL-10+/+RAG-2-/-两种小鼠体内,肿瘤的生长速度相似。可见,肿瘤在野生型小鼠体内生长延迟与获得性免疫相关。我们发现与IL-10-／-小鼠体内肿瘤相比,在野生型小鼠体内生长的肿瘤中有更多的CD8+与CD4+T淋巴细胞浸入。另外,野生型小鼠体内的肿瘤中CD8+T淋巴细胞产生更多的IFN-γ。过继性输注淋巴细胞实验表明,在荷瘤的RAG-2-／-小鼠体内,IL-10-缺失的P1CTL转基因T细胞(能特异性识别肿瘤抗原P1A的CD8+T细胞)的增殖及杀伤肿瘤的能力皆较野生型P1CTL细胞弱。研究表明肿瘤相关髓系细胞(TAMCs)在荷瘤小鼠体内产生大量IL-10。然而,人们对TAMCs产生的IL-10在肿瘤免疫中的作用知之甚少。我们的研究发现阻断IL-10或敲除IL-10基因明显减弱TAMC对肿瘤抗原P1A特异性识别的CD8+T细胞的抑制作用。荷较大肿瘤的IL-10-/-RAG-2-/-小鼠与IL-10+/+RAG-2-/-小鼠体内的TAMCs亚群相似。然而,过继性输注肿瘤抗原P1A特异性的CD8+T细胞在IL-10-／-RAG-2-／-小鼠体内较在IL-10+/+RAG-2-/-小鼠体内增殖更快。另外,IL-10-／-小鼠体内的TAMCs较野生型小鼠体内的TAMCs产生更多的炎症因子。过继性输注CTL治疗在IL-10-/-RAG-2-/-小鼠体内的肿瘤,复发率明显低于IL-10+/+RAG-2-/-小鼠体内肿瘤。因此,IL-10缺陷可将TAMCs从促进肿瘤生长、抑制免疫的细胞转化为抗肿瘤免疫效应细胞。我们比较了IL-10缺陷小鼠与野生型小鼠肿瘤微环境中免疫细胞组分、细胞因子及血管生成,发现IL-10缺陷引发肿瘤内CD4+和CD8+T细胞减少、TAMCs减少,IL-6、IL-17增多,血管生成增多,以上因素综合作用致肿瘤细胞在IL-10小鼠体内生长快于野生小鼠。综上所述,关于IL-10在肿瘤免疫中的作用,我们有两个重要的发现。第一,IL-10缺失的CD8+T细胞在抗肿瘤免疫反应中存在固有性缺陷。第二,IL-10对肿瘤相关髓性细胞是一个关键的转化因子,IL-10缺陷使TAMCs由促肿瘤免疫抑制细胞转化为抗肿瘤免疫效应细胞。同时,我们发现IL-10缺陷可引发肿瘤微环境多种因素变化,肿瘤细胞在IL-10缺陷小鼠体内生长加快是多种因素综合作用的结果。
[Abstract]:Study shows that mice carrying the reporter gene IL-10 on CD8+T lymphocytes and myeloid cells are the main source of IL-10. However, the role of people IL-10 on CD8+T lymphocytes and myeloid cells produced in tumor immunity remain poorly understood. We used a series of transgenic and gene knockout mouse model to study the following three 1.IL-10: influence of defects on the function of CTL; 2. myeloid cells to produce the effect of IL-10 in tumor immunity; the effect of 3.IL-10 on tumor microenvironment formation.
We will plasmacytoma J558 cells in IL-10-/-BALB/c mice and wild type BALB/c mice, found that J558 tumor cells in IL-10- / - mice grow faster than wild-type mice. J558 tumor cells were inoculated in the same IL-10- /-RAG-2-/- and IL-10+/+RAG-2-/- T and lack of B lymphocytes in two mice, the tumor growth rate similar. Obviously, the growth of tumors in wild type mice delay associated with acquired immunity. We found that compared with tumor cells in IL-10- / - mice, CD8+ and CD4+T lymphocytes in the more tumor growth in vivo in wild-type mice. In addition, IFN- gamma produced more CD8+T lymphocytes in wild-type mice tumor. Adoptive transmission showed that lymphocyte injection experiments in RAG-2- / - mice bearing tumor, IL-10- deletion of P1CTL transgenic T cells (specific identification The proliferation of tumor antigen P1A CD8+T cells and the ability to kill tumor are weaker than those of wild type P1CTL cells.
Research shows that tumor associated myeloid cells (TAMCs) have a large number of IL-10. however in tumor bearing mice, little people on TAMCs IL-10 in tumor immunity is known. Our study found that blocking IL-10 or knockout significantly reduced the inhibitory effect of IL-10 gene TAMC on tumor antigen specific P1A identification of CD8+T cells. With larger tumors in IL-10-/-RAG-2-/- mice and IL-10+/+RAG-2-/- mice TAMCs subsets are similar. However, adoptive infusion of tumor antigen specific P1A CD8+T cells in IL-10- / -RAG-2- / - mice than in IL-10+/+RAG-2-/- mice proliferate faster. In addition, IL-10- / - TAMCs mice than wild type mice TAMCs more inflammatory cytokines. Adoptive infusion of CTL treatment in IL-10-/-RAG-2-/- mice of tumor, tumor recurrence rate was significantly lower than in IL-10+/+RAG-2-/- mice. Therefore, IL -10 defects can convert TAMCs cells from tumor growth and immunosuppression to anti-tumor immune response cells.
We compared the immune cell group IL-10 deficient mice and wild-type mice in the tumor microenvironment, cytokines and angiogenesis, IL-10 CD4+ and CD8+T defects caused by tumor cells decreased, TAMCs decreased, IL-6 increased, IL-17, angiogenesis increased, above factors induced by tumor cells in IL-10 mice grew faster than wild mouse.
In summary, on the role of IL-10 in tumor immunity, we have two important findings. First, IL-10 deficient CD8+T cells are intrinsically defective in anti-tumor immune responses. Second, IL-10 of tumor associated myeloid cells is a key transcription factors, IL-10 TAMCs defects from tumor promoting immune suppressive cells into anti-tumor immune effector cells. At the same time, we found that IL-10 can cause changes in tumor microenvironment defects in a variety of factors, the growth of tumor cells in IL-10 deficient mice to speed up is the result of many factors.

【学位授予单位】：中国人民解放军军医进修学院
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R392

【共引文献】