【作者】 郝京生；

【导师】 单保恩；

【作者基本信息】 河北医科大学 ， 免疫学， 2005， 博士

【摘要】 肿瘤是严重影响人类健康的一类疾病，肿瘤的形成和发展与宿主免疫监视功能的异常及肿瘤细胞免疫逃避作用密切相关。目前，手术、化疗和放疗仍是肿瘤的主要治疗方法，但是都存在着局限性。肿瘤的免疫治疗不仅能提高宿主的免疫能力，特异性杀伤肿瘤细胞，而且对正常组织细胞有较少的毒副作用，因此越来越受到人们的重视。细胞因子(cytokine)是由多种细胞所分泌的能调节细胞生长分化、调节免疫功能、参与炎症反应和创伤愈合等作用的一类小分子多肽的统称。利用一些细胞因子能够提高机体免疫功能的作用，将其应用于抗肿瘤治疗，取得了一定的效果。然而，单纯应用细胞因子蛋白的治疗常因其在体内半衰期短，需要大量、持续用药，在收到一定的疗效同时，常产生严重的毒副作用，阻碍了细胞因子的临床应用。因此，寻找新的更为有效的细胞因子及给药途径成为研究热点。由适当的载体如肿瘤细胞、树突状细胞及成纤维细胞等携带细胞因子基因的基因治疗方法是一种备受关注的肿瘤治疗策略之一。携带细胞因子基因的载体在宿主体内可持续产生细胞因子，诱导增强机体免疫功能，杀伤肿瘤细胞，避免了直接使用细胞因子在体内半衰期短、副作用大等缺点。此外，如果载体为肿瘤细胞或负载肿瘤抗原的DC，在产生细胞因子的同时还可提供特异性抗原，可诱导产生特异性抗肿瘤免疫反应。 白细胞介素23(Interleukin，IL-23)是Oppmann等在2000年报告的一个新的细胞因子，IL-23可促进记忆性T细胞增殖，诱导活化的T细胞和树突状细胞产生干扰素-γ(interferon-γ,，IFN-γ,)和白细胞介素12(Interleukin，IL-12)等细胞因子，具有免疫调节活性，参与了自身免疫性疾病、慢性炎症反应和某些感染性疾病的发病和调控。目前，已有研究结果表明，转染IL-23基因的小鼠肿瘤细胞在体内生长速度明显慢于未转染的肿瘤细胞；IL-23可通过诱导和增强小鼠脾细胞CTL活性、促进脾细胞产生IFN-γ等细胞因子而发挥抗肿瘤作用。因此，IL-23有望成为新的免疫治疗因子。由于该因子是新近发现的活性较强的细胞因子，还有许多更多还原

【Abstract】 Tumor is one of the serious diseases threatening human health. Development of tumors is related to a defect of a host immunosurveillance system and an escape mechanism of tumors from host immune responses. At present, operation, chemothreapy and radiotherapy are the main meathods to treat tumors with some limitations. Immunotherapy of tumors which can not only enhance the immune function of host, kill tumor cells in specific way, but also has less side-effects on normal tissues and more and more people have pay attention to immunotherapy. Cytokines possess pleiotropic functions and mediate systemic and local biological actions, which relate to cell growth and differentiation, immune function and inflammation. There are some effects by administration of some cytokines directly in treatment of tumors. Because of the short half-life, large and lasting usage and strong side-effects of cytokines, they are limited in clinical application. Therefore, it is necessary to looking for more effective cytokines and new administration approachs. Cytokine gene therapy is one of the therapeutic strategies of tumors, in which cytokine genes are transduced into some vectors such as tumor cells, dendritic cells and fibroblasts. The vectors carried cytokine genes in host can last production of cytokines that can induce immune responses to tumors and overcome the drawbacks of short half-life, large and lasting usage and strong side effects of cytokines by direct administration. Besides, tumor cells and dendritic cells loaded tumor antigens as cytokine gene therapeutic vectors can provide the antigens to induce specific antitumor responses.Interleukin-23 (IL-23) is a cytokine reported by Oppmann et al in 2000, which can enhance proliferation of memory T cells and production of interferon-γ (IFN-γ) and IL-12 from activated T cells and dendritic cells. IL-23 has also been considered essential to development and control of autoimmune更多还原