Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes.
Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes.
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DOI：
10.1038/s41467-017-01631-z
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发表时间：
2017-11-10
影响因子：
16.6
通讯作者：
Sacha JB
中科院分区：
文献类型：
--
作者：
Burwitz BJ;Wu HL;Abdulhaqq S;Shriver-Munsch C;Swanson T;Legasse AW;Hammond KB;Junell SL;Reed JS;Bimber BN;Greene JM;Webb GM;Northrup M;Laub W;Kievit P;MacAllister R;Axthelm MK;Ducore R;Lewis A;Colgin LMA;Hobbs T;Martin LD;Ferguson B;Thomas CR Jr;Panoskaltsis-Mortari A;Meyers G;Stanton JJ;Maziarz RT;Sacha JB
异基因造血干细胞移植（HSCT）是治疗恶性血液病、先天性代谢缺陷和免疫缺陷疾病的一种非常重要的疗法，但其并发症如移植物抗-宿主疾病（GvHD）限制了存活。开发不会对感染易感性或移植物抗宿主病产生不利影响的抗GvHD疗法肿瘤免疫受到缺乏生理学相关的同种异体HSCT临床前模型的阻碍。在这里，我们展示了一系列不同的临床HSCT结果，包括原发性和继发性移植失败，致死性GvHD，以及在无关的，完全MHC匹配的猕猴中使用降低强度的预处理和动员的外周血HSCT进行的稳定的，无疾病的完全供体移植。他克莫司、移植后环磷酰胺和CD 28阻断剂的抗GvHD预防诱导多谱系、完全供体嵌合和免疫特异性耐受，同时维持病原体特异性免疫。这些结果建立了一种新的临床前同种异体HSCT模型，用于评价GvHD预防和下一代HSCT介导的实体器官耐受性治疗、非恶性血液病治愈和HIV储库清除。恒河猴不是研究异基因造血干细胞移植（allo-HSCT）反应的理想动物，因为复杂的MHC遗传学阻止了完全的MHC匹配。作者在本文中表明，近交的毛里求斯食蟹猴是异基因干细胞移植的一种上级临床前模型，可以模拟人类allo-HSCT的多种临床结果。
Allogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.-tumor immunity are hampered by the lack of a physiologically relevant, preclinical model of allogeneic HSCT. Here we show a spectrum of diverse clinical HSCT outcomes including primary and secondary graft failure, lethal GvHD, and stable, disease-free full donor engraftment using reduced intensity conditioning and mobilized peripheral blood HSCT in unrelated, fully MHC-matched Mauritian-origin cynomolgus macaques. Anti-GvHD prophylaxis of tacrolimus, post-transplant cyclophosphamide, and CD28 blockade induces multi-lineage, full donor chimerism and recipient-specific tolerance while maintaining pathogen-specific immunity. These results establish a new preclinical allogeneic HSCT model for evaluation of GvHD prophylaxis and next-generation HSCT-mediated therapies for solid organ tolerance, cure of non-malignant hematological disease, and HIV reservoir clearance. Rhesus macaques are not ideal for studying response to allogeneic hematopoietic stem cell transplant (allo-HSCT) owing to complex MHC genetics that prevent full MHC-matching. Here the authors show that inbred Mauritian-origin cynomolgus macaques are a superior preclinical model of allogeneic stem cell transplantation that mimics diverse clinical outcomes of human allo-HSCT.
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影响因子：
6.7
作者：
Abdel-Mohsen M;Chavez L;Tandon R;Chew GM;Deng X;Danesh A;Keating S;Lanteri M;Samuels ML;Hoh R;Sacha JB;Norris PJ;Niki T;Shikuma CM;Hirashima M;Deeks SG;Ndhlovu LC;Pillai SK
通讯作者：
Pillai SK
影响因子：
6.4
作者：
Henrich, Timothy J.;Hu, Zixin;Kuritzkes, Daniel R.
通讯作者：
Kuritzkes, Daniel R.
影响因子：
4.3
作者：
Al-Homsi, Ahmad Samer;Roy, Tara S.;Duffner, Ulrich
通讯作者：
Duffner, Ulrich
影响因子：
1.5
作者：
Jaiswal, Sarita Rani;Zaman, Shamsuz;Chakrabarti, Suparno
通讯作者：
Chakrabarti, Suparno
影响因子：
14.9
作者：
Lohse M;Bolger AM;Nagel A;Fernie AR;Lunn JE;Stitt M;Usadel B
通讯作者：
Usadel B