Tim-3调节细胞介导免疫反应在抗恶性疟感染中作用的研究

Malaria is a deadly infectious disease that affects one to two billion people and kills up to one million children yearly. A safe and effective vaccine is essential to achieve significant and sustained reductions in malaria-related morbidity and mortality. Driven by this need, research on the immunology of malaria has tended to focus on antibody dependent immunity, the potential for cellular and innate immune mechanisms, to provide rapid protection against malaria, has been largely neglected. Although cellular immune mechanisms have been regarded as secondary to humoral immunity, there is increasing evidence that shows its critical role in protection against blood stage plasmodium parasites. There are, however, multiple mechanisms of immune deviation, suppression and evolutionary adaptation, which inhibit a sterilizing immunity against the blood stages. Based on these fundamental data, some of the perspectives of new therapeutic tools are critically discussed. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3), originally identified as a Th1-specific cell surface molecule, has received much attention as negative regulator of Th1 mediated immune response in autoimmune disease. Recently studies supported Tim-3 is expressed not only on adaptive immune cells, but also on innate immune cells. Tim-3 induces distinct signaling events which may influence a range of inflammatory conditions, and blockade of Tim-3 signal promotes clearance of intracellular pathogens and even tumor cells. However, study about Tim-3 in parasitic infection has never been reported. Our study revealed elevated Tim-3 expression in PBMCs from Plasmodium falciparum infected patients, compared to healthy subjects. Concerning the critical roles of Tim-3 on T cells and innate immune cells, it is reasonable to suppose that Tim-3 may involve in falciparum malaria. Our study plan to use clinical samples, cellular models and murine models to confirm the effect of Plasmodium falciparum infection on Tim-3 expression, study the mechanism of cell mediated immune response regulated by Tim-3 against falciparum, and further discuss the possibility to prevent falciparum immune escape by Tim-3 signal blockade. The completion of our study will provide new insights into mechanism of immune regulation by Tim-3 in falciparum malaria and also justified the possibility that Tim-3 could serve as a potential target for new therapeutic tools design.

迄今安全有效的疟疾疫苗仍未面世，因此疟疾免疫研究集中于抗体依赖的免疫反应，细胞介导的免疫反应在一定程度上被忽视，然而细胞免疫和固有免疫在疟原虫早期清除和体液免疫的诱导中均发挥重要作用。调节细胞介导免疫反应，阻断疟原虫免疫逃逸，对疟疾防治意义重大。新型免疫调节分子Tim-3在细胞介导的免疫反应调节中发挥重要作用，诱导免疫耐受形成，参与多种病原体感染性疾病的发生，但其在恶性疟发生中的作用尚未见报道。课题组前期研究发现恶性疟感染患者外周血PBMC Tim-3表达水平较健康志愿者显著上调，本项目拟利用临床样本、细胞模型和动物模型，明确Tim-3参与恶性疟感染的发生；深入研究Tim-3调节细胞介导免疫反应在恶性疟感染红内期中的作用及其机制；并进一步探讨阻断Tim-3打破恶性疟原虫免疫逃逸的可行性。本研究将为寄生虫感染免疫提供新的理论，为恶性疟新型免疫治疗方案的建立提供有价值的靶标。

迄今安全有效的疟疾疫苗仍未面世，因此疟疾免疫研究集中于抗体依赖的免疫反应，细胞介导的免疫反应在一定程度上被忽视，然而细胞免疫和固有免疫在疟原虫早期清除和体液免疫的诱导中均发挥重要作用。调节细胞介导免疫反应，阻断疟原虫免疫逃逸，对疟疾防治意义重大。新型免疫调节分子Tim-3在细胞介导的免疫反应调节中发挥重要作用，诱导免疫耐受形成，参与多种病原体感染性疾病的发生，但其在恶性疟发生中的作用尚未见报道。本项目利用流式细胞术对恶性疟患者和健康志愿者外周血和伯氏疟感染小鼠脾脏关键免疫细胞亚群Tim-3表达水平进行了检测，结果显示疟原虫感染能够上调CD4+T、CD8+T细胞和NK细胞Tim-3的表达，而下调单核/巨噬细胞Tim-3的表达。体外利用Tim-3抗体阻断Tim-3信号通路后，能够保护淋巴细胞免于疟原虫感染诱导的凋亡，并促进淋巴细胞细胞因子的产生。静息状态单核/巨噬细胞高表达Tim-3，后者制约单核/巨噬细胞活化，而Tim-3表达减低或信号阻断可促进巨噬细胞的活化，加速虫体清除。体内实验证实，Tim-3信号阻断不仅能促进伯氏疟感染小鼠免疫细胞的活化，且能有效调节宿主的免疫平衡，减轻感染导致的脾脏肿大，从而减轻过度免疫及其导致的脑型疟症状。Tim-3信号阻断在宿主整体炎症反应减轻的条件下，增强了细胞介导的免疫反应，有效促进了虫体的早期清除，减轻宿主的病理改变。综上所述，本项目利用临床样本，体外细胞模型和体内动物模型，对Tim-3在抗疟免疫反应中发挥的作用进行了深入研究，揭示了Tim-3抑制宿主免疫反应造成虫体免疫逃逸的机制，并证实了利用Tim-3抗体阻断Tim-3信号通路能够有效激活细胞介导的免疫反应，促进虫体的早期清除。本项目的研究成果为恶性疟新型免疫治疗方法的设计提供了新的思路。

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