高级检索
中华微生物学和免疫学杂志
期刊首页
过刊列表
高级检索
稿件发表
• 综述 •
ENGLISH ABSTRACT
炎症细胞因子在急性移植物抗宿主病中的作用及机制研究进展
刘霜竹
马守宝
刘海燕
吴德沛
作者及单位信息
·
DOI： 10.3760/cma.j.issn.0254-5101.2017.01.013
Roles of inflammatory cytokines in acute graft-versus-host disease and their mechanisms
Liu Shuangzhu
Ma Shoubao
Liu Haiyan
Wu Depei
Authors Info & Affiliations
Liu Shuangzhu
Institute of Blood and Marrow Transplantation, Department of Hematology; the First Affiliated Hospital of Soochow University; Jiangsu Institute of Hematology and Key Laboratory of Thrombosis and Hemostasis, National Health and Family Planning Commission; Collaborative Innovation Center of Hematology, Suzhou 215006, China
Ma Shoubao
Liu Haiyan
Wu Depei
·
DOI： 10.3760/cma.j.issn.0254-5101.2017.01.013
627
74
0
0
3
0
PDF下载
APP内阅读
摘要

异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation, allo-HSCT)是目前治愈各种恶性血液病及非恶性血液病的有效手段之一。急性移植物抗宿主病(acute graft-versus-host-disease, aGVHD)是allo-HSCT的主要并发症，并且是移植相关死亡的主要原因之一。它的发生发展是一个典型的炎症病理过程，期间会释放大量的炎症细胞因子，构成"细胞因子风暴"，攻击受者靶器官从而形成aGVHD特异性的病理损伤。因此寻找aGVHD特异性的生物标志物，对于aGVHD的迅速、精确的诊断具有重要的意义。本文深入讨论了IL-1β、IL-6、IL-17A和IL-10等4种典型的炎症细胞因子在aGVHD过程中的作用及其机制，旨在为aGVHD的临床防治提供理论指导。

急性移植物抗宿主病;促炎因子;抑炎因子;生物学指标;预测价值
ABSTRACT

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for the treatment of various malignant and non-malignant hematological diseases. Acute graft-verse-host-disease (aGVHD), a major complication following allo-HSCT, is one of the predominant causes of GVHD-related mortality. The development of aGVHD is a typical pathologic process with the release of inflammatory cytokines in great quantities, resulting in the occurrence of " cytokine storm" and causing specific pathological damages by attacking the recipient organ. Therefore, identification of biomarkers specific for aGVHD offers promise to the treatment of aGVHD. In this review, we summarizes the functions of several typical inflammatory cytokines, including IL-1β, IL-6, IL-17A and IL-10, and their mechanisms in the development of aGVHD in order to provide references for the prevention and treatment of aGVHD.

aGVHD;Proinflammator factor;Suppressive factor;Biomarkers;Predictive value
Wu Depei, Email: nc.defudabe.adusiepeduw
National Natural Science Foundation of China (81571556, 81273268, 81500145); China Postdoctoral Science Foundation(7131702415); National High-tech R&D Program of China (863 Program) (2012AA02A505); Natural Science Foundation of Jiangsu Province of China Youth Program(BK201500352); Jiangsu Province′s Key Medical Center (ZX201102)
Copyright by Chinese Medical Association
No content published by the journals of Chinese Medical Association may be reproduced or abridged without authorization. Please do not use or copy the layout and design of the journals without permission.
All articles published represent the opinions of the authors, and do not reflect the official policy of the Chinese Medical Association or the Editorial Board, unless this is clearly specified.
引用本文

刘霜竹,马守宝,刘海燕,等. 炎症细胞因子在急性移植物抗宿主病中的作用及机制研究进展[J]. 中华微生物学和免疫学杂志,2017,37(1)：78-82.

DOI:10.3760/cma.j.issn.0254-5101.2017.01.013

PERMISSIONS

Request permissions for this article from CCC.

评价本文
*以上评分为匿名评价

版权归中华医学会所有。

未经授权，不得转载、摘编本刊文章，不得使用本刊的版式设计。

除非特别声明，本刊刊出的所有文章不代表中华医学会和本刊编委会的观点。

异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation, allo-HSCT)是目前治愈各种恶性血液病及非恶性血液病的有效手段之一。急性移植物抗宿主病(acute graft-versus-host-disease, aGVHD)是allo-HSCT的主要并发症，并且是移植相关死亡的主要原因之一。aGVHD可发生于各种器官，尤其是皮肤、肝、肺和胃肠道。aGVHD发生发展的主要危险因素包括HLA的配型不合、非亲缘骨髓捐赠者、预处理的强度与全身辐射的强度、高龄移植接受者等 [ 1 ]。尽管目前在供体选择、预处理方案以及支持治疗上均有显著进步，仍然有30%～60%的患者会发生aGVHD [ 2 ]。
aGVHD的发生发展是一个典型的炎症病理过程，可以总结为3个连续的阶段 [ 2 , 3 ]：免疫启动阶段、移植前的化疗或放疗预处理造成受者组织损伤，激活危险信号通路，释放促炎细胞因子TNF-α、IL-1和IL-6等；效应T细胞活化与扩增阶段，受者和供者的抗原提呈细胞(APCs)和分泌的促炎细胞因子一同活化供者T细胞并使其扩增为效应T细胞；免疫效应阶段，活化的供体T细胞迁移到aGVHD的靶器官：肝脏、肺、肠和皮肤等，通过Fas/FasL、穿孔素、颗粒酶B以及释放大量促炎细胞因子如IL-2、IFN-γ、TNF-α，构成"细胞因子风暴"，攻击受者靶器官从而形成aGVHD特异性的病理损伤，机体的损伤可进一步活化T细胞，形成一个正反馈的恶性循环。aGVHD一旦发生就很难有效控制。因此，控制炎症因子风暴，下调机体的免疫应答，是治疗aGVHD的有效策略。本文深入讨论了IL-1β、IL-6、IL-17A和IL-10等炎症细胞因子在aGVHD过程中的作用及其机制，旨在为aGVHD的临床防治提供理论指导。
试读结束，您可以通过登录机构账户或个人账户后获取全文阅读权限。
参考文献
[1]
Magenau J , Runaas L , Reddy P . Advances in understanding the pathogenesis of graft-versus-host disease[J]. Br J Haematol, 2016,173(2):190-205. DOI: 10.1111/bjh.13959 .
返回引文位置Google Scholar
百度学术
万方数据
[2]
Holtan SG , Pasquini M , Weisdorf DJ . Acute graft-versus-host disease: a bench-to-bedside update[J]. Blood, 2014,124(3):363-373. DOI: 10.1182/blood-2014-01-514786 .
返回引文位置Google Scholar
百度学术
万方数据
[3]
Chen Y , Zhao Y , Cheng Q ,et al. The role of intestinal microbiota in acute graft-versus-host disease[J]. J Immunol Res, 2015,2015:145859. DOI: 10.1155/2015/145859 .
返回引文位置Google Scholar
百度学术
万方数据
[4]
Jokela T , Oikari S , Takabe P ,et al. Interleukin-1β-induced reduction of CD44 Ser-325 phosphorylation in human epidermal keratinocytes promotes CD44 homomeric complexes, binding to ezrin, and extended, monocyte-adhesive hyaluronan coats[J]. J Biol Chem, 2015,290(19):12379-12393. DOI: 10.1074/jbc.M114.620864 .
返回引文位置Google Scholar
百度学术
万方数据
[5]
Jankovic D , Ganesan J , Bscheider M ,et al. The Nlrp3 inflammasome regulates acute graft-versus-host disease[J]. J Exp Med, 2013,210(10):1899-1910. DOI: 10.1084/jem.20130084 .
返回引文位置Google Scholar
百度学术
万方数据
[6]
Park MJ , Lee SH , Lee SH ,et al. IL-1 receptor blockade alleviates graft-versus-host disease through downregulation of an interleukin-1β-dependent glycolytic pathway in Th17 cells[J]. Mediators Inflamm, 2015,2015:631384. DOI: 10.1155/2015/631384 .
返回引文位置Google Scholar
百度学术
万方数据
[7]
Gao HL , Sun AN , Han Y ,et al. Clinical significance of TNF-alpha, IL-1beta and IFN-gamma levels at early phase after allogeneic hematopoietic stem cell transplantation[J]. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2009,17(5):1321-1325.
返回引文位置Google Scholar
百度学术
万方数据
[8]
Antin JH , Weisdorf D , Neuberg D ,et al. Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation[J]. Blood, 2002,100(10):3479-3482. DOI: 10.1182/blood-2002-03-0985 .
返回引文位置Google Scholar
百度学术
万方数据
[9]
Tanaka T , Narazaki M , Kishimoto T . Therapeutic targeting of the interleukin-6 receptor[J]. Annu Rev Pharmacol Toxicol, 2012,52:199-219. DOI: 10.1146/annurev-pharmtox-010611-134715 .
返回引文位置Google Scholar
百度学术
万方数据
[10]
Bettelli E , Carrier Y , Gao W ,et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J]. Nature, 2006,441(7090):235-238. DOI: 10.1038/nature04753 .
返回引文位置Google Scholar
百度学术
万方数据
[11]
Min CK , Lee WY , Min DJ ,et al. The kinetics of circulating cytokines including IL-6, TNF-alpha, IL-8 and IL-10 following allogeneic hematopoietic stem cell transplantation[J]. Bone Marrow Transplant, 2001,28(10):935-940. DOI: 10.1038/sj.bmt.1703258 .
返回引文位置Google Scholar
百度学术
万方数据
[12]
Jing Y , Yu L , Guo GH ,et al. Change of IL-4 and IL-6 levels in blood plasma of patients transplanted with allogeneic hematopoietic stem cells determined by protein chip and its relationship with aGVHD[J]. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2008,16(2):360-363.
返回引文位置Google Scholar
百度学术
万方数据
[13]
McDonald GB , Tabellini L , Storer BE ,et al. Plasma biomarkers of acute GVHD and nonrelapse mortality: predictive value of measurements before GVHD onset and treatment[J]. Blood, 2015,126(1):113-120. DOI: 10.1182/blood-2015-03-636753 .
返回引文位置Google Scholar
百度学术
万方数据
[14]
Toren A , Novick D , Or R ,et al. Soluble interleukin-6 receptors in hematology patients undergoing bone marrow transplantation[J]. Transplantation, 1996,62(1):138-142.
返回引文位置Google Scholar
百度学术
万方数据
[15]
Chen X , Das R , Komorowski R ,et al. Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease[J]. Blood, 2009,114(4):891-900. DOI: 10.1182/blood-2009-01-197178 .
返回引文位置Google Scholar
百度学术
万方数据
[16]
Tawara I , Koyama M , Liu C ,et al. Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation[J]. Clin Cancer Res, 2011,17(1):77-88. DOI: 10.1158/1078-0432.CCR-10-1198 .
返回引文位置Google Scholar
百度学术
万方数据
[17]
Betts BC , St Angelo ET , Kennedy M ,et al. Anti-IL6-receptor-alpha (tocilizumab) does not inhibit human monocyte-derived dendritic cell maturation or alloreactive T-cell responses[J]. Blood, 2011,118(19):5340-5343. DOI: 10.1182/blood-2011-06-363390 .
返回引文位置Google Scholar
百度学术
万方数据
[18]
Kennedy GA , Varelias A , Vuckovic S ,et al. Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial[J]. Lancet Oncol, 2014,15(13):1451-1459. DOI: 10.1016/S1470-2045(14)71017-4 .
返回引文位置Google Scholar
百度学术
万方数据
[19]
Liu Y , Cai Y , Dai L ,et al. The expression of Th17-associated cytokines in human acute graft-versus-host disease[J]. Biol Blood Marrow Transplant, 2013,19(10):1421-1429. DOI: 10.1016/j.bbmt.2013.06.013 .
返回引文位置Google Scholar
百度学术
万方数据
[20]
Dander E , Balduzzi A , Zappa G ,et al. Interleukin-17-producing T-helper cells as new potential player mediating graft-versus-host disease in patients undergoing allogeneic stem-cell transplantation[J]. Transplantation, 2009,88(11):1261-1272. DOI: 10.1097/TP.0b013e3181bc267e .
返回引文位置Google Scholar
百度学术
万方数据
[21]
Ratajczak P , Janin A , Peffault de Latour R ,et al. Th17/Treg ratio in human graft-versus-host disease[J]. Blood, 2010,116(7):1165-1171. DOI: 10.1182/blood-2009-12-255810 .
返回引文位置Google Scholar
百度学术
万方数据
[22]
Carlson MJ , West ML , Coghill JM ,et al. In vitro-differentiated Th17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations [J]. Blood, 2009,113(6):1365-1374. DOI: 10.1182/blood-2008-06-162420 .
返回引文位置Google Scholar
百度学术
万方数据
[23]
Yu Y , Wang D , Liu C ,et al. Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice[J]. Blood, 2011,118(18):5011-5020. DOI: 10.1182/blood-2011-03-340315 .
返回引文位置Google Scholar
百度学术
万方数据
[24]
Yi T , Zhao D , Lin CL ,et al. Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease[J]. Blood, 2008,112(5):2101-2110. DOI: 10.1182/blood-2007-12-126987 .
返回引文位置Google Scholar
百度学术
万方数据
[25]
Iclozan C , Yu Y , Liu C ,et al. T helper17 cells are sufficient but not necessary to induce acute graft-versus-host disease[J]. Biol Blood Marrow Transplant, 2010,16(2):170-178. DOI: 10.1016/j.bbmt.2009.09.023 .
返回引文位置Google Scholar
百度学术
万方数据
[26]
Kappel LW , Goldberg GL , King CG ,et al. IL-17 contributes to CD4-mediated graft-versus-host disease[J]. Blood, 2009,113(4):945-952. DOI: 10.1182/blood-2008-08-172155 .
返回引文位置Google Scholar
百度学术
万方数据
[27]
Cai Y , Ma S , Liu Y ,et al. Adoptively transferred donor IL-17-producing CD4 ＋ T cells augment, but IL-17 alleviates, acute graft-versus-host disease [J]. Cell Mol Immunol, 2016. DOI: 10.1038/cmi.2016.37 .
返回引文位置Google Scholar
百度学术
万方数据
[28]
Cho IH , Song YK , Kim MG ,et al. Association between interleukin-10 promoter gene polymorphisms and acute graft-versus-host disease after hematopoietic stem cell transplantation: a systematic review and meta-analysis[J]. Hematology, 2015,20(3):121-128. DOI: 10.1179/1607845414Y.0000000183 .
返回引文位置Google Scholar
百度学术
万方数据
[29]
Holler E , Roncarolo MG , Hintermeier-Knabe R ,et al. Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation[J]. Bone Marrow Transplant, 2000,25(3):237-241.
返回引文位置Google Scholar
百度学术
万方数据
[30]
Weston LE , Geczy AF , Briscoe H . Production of IL-10 by alloreactive sibling donor cells and its influence on the development of acute GVHD[J]. Bone Marrow Transplant, 2006,37(2):207-212. DOI: 10.1038/sj.bmt.1705218 .
返回引文位置Google Scholar
百度学术
万方数据
[31]
Rowe V , Banovic T , MacDonald KP ,et al. Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation[J]. Blood, 2006,108(7):2485-2492. DOI: 10.1182/blood-2006-04-016063 .
返回引文位置Google Scholar
百度学术
万方数据
[32]
Weber M , Stein P , Prüfer S ,et al. Donor and host B cell-derived IL-10 contributes to suppression of graft-versus-host disease[J]. Eur J Immunol, 2014,44(6):1857-1865. DOI: 10.1002/eji.201344081 .
返回引文位置Google Scholar
百度学术
万方数据
[33]
Tawara I , Sun Y , Liu C ,et al. Donor- but not host-derived interleukin-10 contributes to the regulation of experimental graft-versus-host disease[J]. J Leukoc Biol, 2012,91(4):667-675. DOI: 10.1189/jlb.1011510 .
返回引文位置Google Scholar
百度学术
万方数据
[34]
Bacchetta R , Lucarelli B , Sartirana C ,et al. Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T cells[J]. Front Immunol, 2014,5:16. DOI: 10.3389/fimmu.2014.00016.eCollection2014 .
返回引文位置Google Scholar
百度学术
万方数据
[35]
Yeh SP , Liao YM , Lo WJ ,et al. Kinetics of T helper subsets and associated cytokines correlate well with the clinical activity of graft-versus-host disease[J]. PLoS One, 2012,7(9):e44416. DOI: 10.1371/journal.pone.0044416 .
返回引文位置Google Scholar
百度学术
万方数据
[36]
Blazar BR , Taylor PA , Panoskaltsis-Mortari A ,et al. Interleukin-10 dose-dependent regulation of CD4 ＋ and CD8 ＋ T cell-mediated graft-versus-host disease [J]. Transplantation, 1998,66(9):1220-1229.
返回引文位置Google Scholar
百度学术
万方数据
[37]
Abraham S , Choi JG , Ye C ,et al. IL-10 exacerbates xenogeneic GVHD by inducing massive human T cell expansion[J]. Clin Immunol, 2015,156(1):58-64. DOI: 10.1016/j.clim.2014.11.004 .
返回引文位置Google Scholar
百度学术
万方数据
[38]
Lu Y , Waller EK . Dichotomous role of interferon-gamma in allogeneic bone marrow transplant[J]. Biol Blood Marrow Transplant, 2009,15(11):1347-1353. DOI: 10.1016/j.bbmt.2009.07.015 .
返回引文位置Google Scholar
百度学术
万方数据
[39]
Lu Y , Giver CR , Sharma A ,et al. IFN-γ and indoleamine 2，3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity[J]. Blood, 2012,119(4):1075-1085. DOI: 10.1182/blood-2010-12-322891 .
返回引文位置Google Scholar
百度学术
万方数据
[40]
Koenecke C , Lee CW , Thamm K ,et al. IFN-γ production by allogeneic Foxp3 ＋ regulatory T cells is essential for preventing experimental graft-versus-host disease [J]. J Immunol, 2012,189(6):2890-2896. DOI: 10.4049/jimmunol.1200413 .
返回引文位置Google Scholar
百度学术
万方数据
[41]
Choi J , Ziga ED , Ritchey J ,et al. IFNγR signaling mediates alloreactive T-cell trafficking and GVHD[J]. Blood, 2012,120(19):4093-4103. DOI: 10.1182/blood-2012-01-403196 .
返回引文位置Google Scholar
百度学术
万方数据
[42]
Sun K , Hsiao HH , Li M ,et al. IFN-γ receptor-deficient donor T cells mediate protection from graft-versus-host disease and preserve graft-versus-tumor responses after allogeneic bone marrow transplantation[J]. J Immunol, 2012,189(4):2033-2042. DOI: 10.4049/jimmunol.1102853 .
返回引文位置Google Scholar
百度学术
万方数据
[43]
Chen YB , Cutler CS . Biomarkers for acute GVHD: can we predict the unpredictable？[J]. Bone Marrow Transplant, 2013,48(6):755-760. DOI: 10.1038/bmt.2012.143 .
返回引文位置Google Scholar
百度学术
万方数据
[44]
Choi SW , Reddy P . Current and emerging strategies for the prevention of graft-versus-host disease[J]. Nat Rev Clin Oncol, 2014,11(9):536-547. DOI: 10.1038/nrclinonc.2014.102 .
返回引文位置Google Scholar
百度学术
万方数据
[45]
Choi SW , Stiff P , Cooke K ,et al. TNF-inhibition with etanercept for graft-versus-host disease prevention in high-risk HCT: lower TNFR1 levels correlate with better outcomes[J]. Biol Blood Marrow Transplant, 2012,18(10):1525-1532. DOI: 10.1016/j.bbmt.2012.03.013 .
返回引文位置Google Scholar
百度学术
万方数据
[46]
Couriel DR , Saliba R , de Lima M ,et al. A phase III study of infliximab and corticosteroids for the initial treatment of acute graft-versus-host disease[J]. Biol Blood Marrow Transplant, 2009,15(12):1555-1562. DOI: 10.1016/j.bbmt.2009.08.003 .
返回引文位置Google Scholar
百度学术
万方数据
[47]
Pierini A , Strober W , Moffett C ,et al. TNF-α priming enhances CD4 ＋ FoxP3 ＋ regulatory T-cell suppressive function in murine GVHD prevention and treatment [J]. Blood, 2016,128(6):866-871. DOI: 10.1182/blood-2016-04-711275 .
返回引文位置Google Scholar
百度学术
万方数据
[48]
Liu Y , Wu Y , Wang Y ,et al. IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects[J]. Leukemia, 2015,29(4):939-946. DOI: 10.1038/leu.2014.310 .
返回引文位置Google Scholar
百度学术
万方数据
[49]
Zhang X , Zhou Y , Xu L ,et al. Reduced IL-35 levels are associated with increased platelet aggregation and activation in patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation[J]. Ann Hematol, 2015,94(5):837-845. DOI: 10.1007/s00277-014-2278-7 .
返回引文位置Google Scholar
百度学术
万方数据
[50]
Zhang XH , Zhou Y , Zhang JM ,et al. IL-35 inhibits acute graft-versus-host disease in a mouse model[J]. Int Immunopharmacol, 2015,29(2):383-392. DOI: 10.1016/j.intimp.2015.10.025 .
返回引文位置Google Scholar
百度学术
万方数据
[51]
Antin JH , Weinstein HJ , Guinan EC ,et al. Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease[J]. Blood, 1994,84(4):1342-1348.
返回引文位置Google Scholar
百度学术
万方数据
[52]
Drobyski WR , Pasquini M , Kovatovic K ,et al. Tocilizumab for the treatment of steroid refractory graft-versus-host disease[J]. Biol Blood Marrow Transplant, 2011,17(12):1862-1868. DOI: 10.1016/j.bbmt.2011.07.001 .
返回引文位置Google Scholar
百度学术
万方数据
备注信息
A
吴德沛，Email： nc.defudabe.adusiepeduw，电话：0512-67781851
B
国家自然科学基金 (81571556，81273268，81500145)
中国博士后科学基金项目 (7131702415)
国家高科技研究发展计划（863计划） (2012AA02A505)
江苏省自然科学基金青年项目 (BK201500352)
江苏省科教兴卫工程——临床医学中心 (ZX201102)
评论 （0条）
注册
登录
时间排序
暂无评论，发表第一条评论抢沙发
最新推荐
更多
神经免疫在抑郁症发病机制中的研究进展
孙瑞 等
中华精神科杂志 2023,56(02)
顺铂相关急性肾损伤的发病机制及其治疗的研究进展
周钰 等
中华肾脏病杂志 2022,38(11)
线粒体DNA在慢性肝病发病机制中作用的研究进展
张兴 等
中华肝脏病杂志 2022,30(04)
中国异基因造血干细胞移植治疗血液系统疾病专家共识（Ⅲ）——急性移植物抗宿主病（2020年版）
中华医学会血液学分会干细胞应用学组
中华血液学杂志 2020,41(07)
MedAI助手（体验版）
文档即答
智问智答
机器翻译
回答内容由人工智能生成，我社无法保证其准确性和完整性，该生成内容不代表我们的态度或观点，仅供参考。
生成快照
文献快照

你好，我可以帮助您更好的了解本文，请向我提问您关注的问题。

0/2000

《中华医学会杂志社用户协议》 | 《隐私政策》

《SparkDesk 用户协议》 | 《SparkDesk 隐私政策》

网信算备340104764864601230055号 | 网信算备340104726288401230013号

技术支持：

历史对话
本文全部
还没有聊天记录
设置
模式
纯净模式沉浸模式
字号
小中大