三种细胞因子与白血病异基因造血干细胞移植后移植物抗宿主病的关系(英文)

Association of three cytokines with graft versus host disease after allogeneic hematopoietic stem cell transplantation for leukemia

背景：目前转化生长因子α与移植物抗宿主病关系的报道较少，急、慢性移植物抗宿主病患者转化生长因子α与多种因子联合的检测值得研究。目的：分析血清肿瘤坏死因子α、白细胞介素4和转化生长因子α在白血病患者异基因造血干细胞移植后的变化与发生移植物抗宿主病轻重程度的关系。设计：病例对照观察。单位：解放军总医院第二附属医院器官移植中心血液科及解放军总医院第二附属医院核医学科。对象：选择2005—06／2007—06在解放军总医院第二附属医院器官移植中心血液科及解放军307医院移植科住院首次接受异基因造血干细胞移植的42例白血病患者，男23例，女19例，年龄16～68岁，平均35岁。其中急性粒细胞性白血病12例，急性淋巴细胞性白血病15例，慢性粒细胞性白血病15例，移植患者中行外周血移植37例、骨髓移植5例。异基因造血干细胞移植后发生急性移植物抗宿主病20例（Ⅰ～Ⅱ度18例、Ⅲ～Ⅳ度3例），未发生急性移植物抗宿主病21例，发生慢性移植物抗宿主病14例（局限型5例、广泛型9例），未发生慢性移植物抗宿主病28例。选择30名同期到院健康体检者为正常对照组，男18名，女12名，年龄20～70岁，平均44岁。所有受试对象均对实验项目知情同意，实验经过医院伦理委员会批准。方法：用放射免疫分析法检测并比较白血病异基因造血干细胞移植患者及正常对照者血清肿瘤坏死因子α、白细胞介素4和转化生长因子α水平，同时比较移植后发生或未发生急性移植物抗宿主病、发生或未发生慢性移植物抗宿主病及发生轻重程度的白血病异基因造血干细胞移植患者3种细胞因子水平。主要观察指标：血清肿瘤坏死因子α、白细胞介素4、转化生长因子α水平比较。结果：白血病患者42例及健康对照者30名均进入结果分析。①急、慢性移植物抗宿主病患者血清肿瘤坏死因子α、白细胞介素4、转化生长因子α水平均高于正常对照组，差异有显著性意义（P〈0．05～0．01），未发生急性移植物抗宿主病患者血清肿瘤坏死因子α、白细胞介素-4水平高于正常对照组，差异有显著性意义（P〈0．01，0．05）。急性移植物抗宿主病患者血清肿瘤坏死因子α、白细胞介素4、转化生长因子α水平高于未发生者，差异有显著性意义（P〈0．05）。慢性移植物抗宿主病患者血清肿瘤坏死因子α、白细胞介素4、转化生长因子α水平高于未发生者，差异有显著性意义（P〈0.05）。②急性移植物抗宿主病Ⅲ-Ⅳ度或慢性移植物抗宿主病广泛型患者血清肿瘤坏死因子α及转化生长因子α水平均高于急性移植物抗宿主病Ⅰ—Ⅱ0或慢性移植物抗宿主病局限型，差异有显著性意义（P〈0．05～0．01）。结论：异基因造血干细胞移植术后动态监测肿瘤坏死因子α、白细胞介素4和转化生长因子α水平变化有助于对发生急性或慢性移植物抗宿主病预测，对判断移植物抗宿主病的轻重程度有一定意义。

BACKGROUND： Recently, a few studies have reported the correlation between transforming growth factor- α （TGF- α ） and graft-versus-host disease （GVHD）; however, the combination of TGF- α with other cytokines in patients with chronic or acute GVHD requires further study. OBJECTIVE： To analyze the changes of serum tumor necrosis factor- α （TNF- α ）, interleukin-4 （IL-4）, and transforming growth factor- α （TGF- α ） in leukemic patients after allogeneic hematopoietic stem cell transplantation （Allo-HSCT） and investigate the effects of these cytokines on different grades of GVHD. DESIGN： Case control study. SETTING： Department of Hematology, Organ Transplantation Center, the Second Affiliated Hospital, General Hospital of Chinese PLA; Department of Nuclear Medicine, the Second Affiliated Hospital, General Hospital of Chinese PLA. PARTICIPANTS： Forty-two leukemic patients （23 males and 19 females, 16-68 years old, mean age of 35 years） who underwent Allo-HSCT for the first time were selected from the Department of Hematology, Organ Transplantation Center, the Second Affiliated Hospital, General Hospital of Chinese PLA and Department of Transplantation, the 307 Hospital of Chinese PLA from June 2005 to June 2007. Twelve patients had acute granulocytic leukemia （AGL）, fifteen patients had acute lymphocytic leukemia （ALL）, and fifteen patients had chronic granulocytic leukemia （CGL）. Among the 42 patients, 37 underwent peripheral blood transplantation and five received bone marrow transplantation. Twenty-one patients had acute GVHD （18 cases in grades Ⅰ-Ⅱ and three cases in grades Ⅲ-Ⅳ） after Allo-HSCT, but the other 21 patients did not. Fourteen patients had chronic GVHD （five cases of limited type and nine cases of extensive type）, but the other 28 patients did not. An additional 30 healthy subjects （18 males and 12 females, 20-70 years old, mean age of 44 years） were collected as a normal control group. All patients provided confirmed consent, and the study was approved by the local ethics committee. METHODS： Levels of serum TNF-α, IL-4, and TGF-α in leukemic patients with Allo-HSCT and normal subjects were measured by radio-immuno-assay, the cytokines levels of the patients with/without acute GVHD, of those with/without chronic GVHD and of different grades of GVHD were compared. MAIN OUTCOME MEASURES： Comparisons of serum TNF- α, IL-4, and TGF- α among the groups. RESULTS： All 42 leukemic patients and 30 healthy subjects were included in the final analysis. Levels of TNF- α, IL-4, and TGF- α in patients with acute or chronic GVHD were significantly higher than those in the normal subjects （P 〈 0.05-0.01）. Levels of TNF- α and IL-4 in patients without acute GVHD were significantly higher than those in the normal subjects （P 〈 0.01, 0.05）. Levels of TNF- α, IL-4, and TGF- α in patients with acute GVHD were significantly higher than those in patients without acute GVHD （P 〈 0.05）. Levels of TNF- α, IL-4, and TGF- α in patients with chronic GVHD were significantly higher than those in patients without chronic GVHD （P 〈 0.05）. Levels of serum TNF- α and TGF- α in patients with acute GVHD of grades Ⅲ-Ⅳ or chronic GVHD of extensive type were significantly higher than those in patients with acute GVHD of grades Ⅰ-Ⅱ or chronic GVHD of limited type （P 〈 0.05-0.01 ）. CONCLUSION： After Allo-HSCT, dynamically monitoring changes of levels of TNF- α, IL-4, and TGF- α may serve as a possible means of predicting the onset of acute or chronic GVHD and may contribute considerably to deciding clinical severity of GVHD.