共刺激分子B7-H3在急性白血病发病中的作用及机制的研究

B7-H3 is a newly identified co-stimulatory molecule of the B7/CD28 super family, which can promote T cell activation. Recent reports showed that B7-H3 molecule is expressed in several human tumor cells, stimulating and/or inhibiting the tumor immunity. However, our knowledge about its role in the pathogenesis of tumor is paucity. Our previous study demonstrated that B7-H3 surface antigen can be detected expressing on blast cells of newly diagnosed patients with acute leukemia (AL), and mouse anti-human antibody (mAb B7-H3) could inhibit the proliferation of myeloid leukemia cell lines including U937 and K562. Furthermore, the expression of B7-H3 was significantly associated with shorter progression free survival and overall survival in patients with AL. So we hypothesized that B7-H3 expression in AL may predict an unfavorable outcome. In this study, we will explore the pathogenic role and molecular mechanism of B7-H3 molecule in AL at the different levels including molecular biology, cell lines, tumor-bearing animal models, AL patients' sample detection and clinical follow-up, which can provide new theoretical basis for the prognosis and treatment of AL.

B7-H3分子是B7/CD28超家族中最新发现的促进T细胞活化的共刺激分子。最近报道有几种人类肿瘤细胞可表达B7-H3分子，B7-H3分子具有刺激和/或抑制肿瘤免疫的双重功能，但B7-H3分子对肿瘤致病机制所知甚少。我们的研究发现在初诊急性白血病（AL）患者的白血病细胞上可以检测到B7-H3分子的表达，抑制性鼠抗人mAb B7-H3与U937和K562细胞表面的B7-H3分子结合后可抑制这2种细胞的增殖，并观察到B7-H3分子阳性表达的AL患者的无进展生存期及总体生存率明显低于B7-H3阴性AL患者，由此我们提出假说B7-H3分子可能是AL的致病机制之一。为了验证这一假说，我们将同时从分子、细胞、荷瘤动物模型、大系列AL患者标本检测及临床随访等不同层面，深入探讨B7-H3分子在AL中的致病作用及涉及的分子机制，为AL的预后判断及治疗提供新的理论依据。

B7-H3分子是B7/CD28超家族中被新发现的促进T细胞活化的共刺激分子；多种人类肿瘤细胞可表达B7-H3分子。本课题组发表的B7-H3与白血病的研究已被用引14次。① 证明了白血病细胞株上有B7-H3分子的表达：抑制性鼠抗人mAb B7-H3抗体与 U937和K562细胞表面的B7-H3分子结合后可抑制这2种细胞的增殖。② 在初诊急性白血病（AL）患者的白血病细胞上检测到B7-H3分子的表达。③ 用流式检测167例初诊AL患者的白血病原始细胞B7-H3+ 阳性率是44.8%，不同个体表达率从0-74.8%。B7-H3阳性表达与年龄、性别、白细胞计数没有相关性。④ 在初诊AL患者中，B7-H3+表达率高表达于WBC>30×10 9/L；CD34+AL患者B7-H3阳性表达率明显高于CD34-患者；染色体预后差组(Ph+或复杂核型)的B7-H3+表达率明显高于染色体预后好及中等预后组。⑤B7-H3+AL患者的无进展生存期及总体生存率(OS)明显低于B7-H3-AL患者（7.4月 vs 15.2月）和（9.8月 vs 17.8月）。⑥ 已知B7-H3分子是B7/CD28超家族成员之一，采用FCM、RT-PCR及激光共聚焦显微方法证明了U937细胞组成性共表达共刺激分子4-1BBL和CD28i 分子；U937细胞用mAb1F1刺激30min后，4-1BBL和CD28i在U937细胞表面聚集形成斑块 状的共定位，提示CD28i分子可能参与了4-1BBL逆向信号的传导。⑦探讨血清sCD25（T细胞免疫）在AL中的临床意义： a. 97例初诊AL患者血清sCD25水平明显高于正常对照组；b.初诊M3组明显低于M2及非M2/M3组；初诊低/中危组（AML）+标危组（ALL）组明显低于高危组AL。c. 完全缓解后明显低于初诊时，复发/难治组较初诊组无明显差别；d. 初诊时sCD25 >4000pg/ml的患者OS期较短。