Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease.
Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease.
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DOI：
10.1056/nejmoa1201248
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发表时间：
2012-07-12
期刊：
影响因子：
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通讯作者：
Porter DL
中科院分区：
文献类型：
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作者：
Reshef R;Luger SM;Hexner EO;Loren AW;Frey NV;Nasta SD;Goldstein SC;Stadtmauer EA;Smith J;Bailey S;Mick R;Heitjan DF;Emerson SG;Hoxie JA;Vonderheide RH;Porter DL
移植物抗宿主病(GVHD)是异基因造血干细胞移植(HSCT)成功的主要障碍。趋化因子受体CCR5似乎在同种异体反应中发挥作用。我们测试了阻断CCR5是否安全并限制人类GVHD。我们检测了CCR5拮抗剂马拉韦罗对淋巴细胞功能和趋化作用的影响。然后，我们招募了38名高危患者参加降低强度的异基因造血干细胞移植的单组阶段1和2研究，该研究结合了马拉韦罗和标准的GVHD预防措施。马拉韦罗在体外抑制CCR5内化和淋巴细胞趋化，而不损害T细胞功能或造血细胞集落形成。在可评估的35例患者中，II~IV级急性移植物抗宿主病(GVHD)的累积发生率(±SE)在第100天为14.7±6.2%，在第180天为23.6±7.4%。急性肝脏和肠道移植物抗宿主病在第100天前未见，在第180天前仍很少见，导致在第180天发生III级或IV级移植物抗宿主病的累积发生率较低(5.9±4.1%)。未复发的1年死亡率为11.7±5.6%，无过多复发或感染。接受马拉韦罗治疗的患者的血清阻止CCR5被CCL5内化，并在体外阻断T细胞的趋化作用，提供了抗趋化活性的证据。在这项研究中，抑制淋巴细胞转运是预防内脏急性GVHD的一种特定且潜在有效的新策略。(由辉瑞和其他公司资助；ClinicalTrials.gov编号，NCT00948753。)
Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic stem-cell transplantation (HSCT). The chemokine receptor CCR5 appears to play a role in alloreactivity. We tested whether CCR5 blockade would be safe and limit GVHD in humans. We tested the in vitro effect of the CCR5 antagonist maraviroc on lymphocyte function and chemotaxis. We then enrolled 38 high-risk patients in a single-group phase 1 and 2 study of reduced-intensity allogeneic HSCT that combined maraviroc with standard GVHD prophylaxis. Maraviroc inhibited CCR5 internalization and lymphocyte chemotaxis in vitro without impairing T-cell function or formation of hematopoietic-cell colonies. In 35 patients who could be evaluated, the cumulative incidence rate (±SE) of grade II to IV acute GVHD was low at 14.7±6.2% on day 100 and 23.6±7.4% on day 180. Acute liver and gut GVHD were not observed before day 100 and remained uncommon before day 180, resulting in a low cumulative incidence of grade III or IV GVHD on day 180 (5.9±4.1%). The 1-year rate of death that was not preceded by disease relapse was 11.7±5.6% without excessive rates of relapse or infection. Serum from patients receiving maraviroc prevented CCR5 internalization by CCL5 and blocked T-cell chemotaxis in vitro, providing evidence of antichemotactic activity. In this study, inhibition of lymphocyte trafficking was a specific and potentially effective new strategy to prevent visceral acute GVHD. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00948753.)