Blood:吡非尼酮具有治疗cGVHD引起的闭塞性细支气管炎的潜力

2017-05-05 MedSci MedSci原创

这个新发现是非常重要的,其原因有两个:(1)对于不能耐受连续给药的患者,间断性使用吡非尼酮但不影响药物功效,以及(2)TGF-β抑制的时机。因为TGF-β是重要的调节性细胞因子抑制免疫反应,传统的在移植后使用中和TGF-β抗体抑制其活性可能通过促进细胞毒性而产生有害后果,而HSCT后期产生的TGF-β已被发现显著驱动cGVHD。因此,推测移植后期使用吡非尼酮对TGF-β“晚期”抑制,不会影响TGF

cGVHD(chronic graft vs host disease)是一种接受同种异体造血干细胞移植(HSCT)患者的频繁且致命的并发症。早些时候,人们普遍认为在移植后100天内出现的移植细胞对抗宿主病(GVHD)是急性GVHD(aGVHD),而超过“100天”的GVHD是慢性GVHD(cGVHD)。现在,这个主观的以一百天作为截断被认为是过度简化,因为已经知道cGVHD的症状可以与aGVHD同时重叠并存。最近以来的一些研究表明,cGVHD是由T细胞引发的,主要是分泌细胞激素IL17的CD4+T细胞17(Th17)和CD8 + T(Tc17)细胞,其涉及促进卵泡T(Follicular T helper cells)细胞异常升高的,在生发中心(germinal center)最终促进产生针对同种异体和自身的抗体。

临床上,cGVHD主要表现为硬皮病(scleroderma),闭塞性细支气管炎(bronchiolitis obliterans)和口腔扁平苔藓样病变(oral lichen planus–like lesions)。cGVHD的发病率和死亡率有显着的关联,特别是闭塞性细支气管炎患者的5年死亡率为41%。这些不良结果强调需要开发有效的抗cGVHD疗法。

在本期Blood杂志中,Jing Du及其同事发现吡非尼酮(Pirfenidone)在模拟慢性移植物抗宿主病(cGVHD)引起的闭塞性细支气管炎模型中具有显着的治疗效果。他们的数据支持使用吡非尼酮作为cGVHD治疗的早期临床试验的实验新药。

吡非尼酮是口服抗纤维化治疗药物,最近被美国食品和药物管理局(FDA)批准用于治疗特发性肺纤维化,其中已经显示吡非尼酮减少疾病进展并增加人的肺功能。多项报导还显示出吡非尼酮在鼠肺同种异体移植/肺纤维化模型中起到保护的作用。鉴于这些互补性发现,调查吡非尼酮是否具有对cGVHD的任何疗效是非常合理的,特别是在闭塞性细支气管炎的模型中。

研究人员首先将B6种的小鼠的支气管移植到B10中模拟闭塞性细支气管炎模型,并证明吡非尼酮具有治疗和逆转肺纤维化的功能。分子机理上,研究人员表明,活化的M2巨噬细胞是肺纤维化的主要驱动因素,吡非尼酮显着降低M2巨噬细胞浸润到肺中以及M2巨噬细胞介导的TGF-β产生。吡非尼酮治疗也导致生发中心B细胞和T helper细胞减少,这些细胞是产生自身/同种异体的抗体及其驱动的病理学的重要介质。研究人员还发现,在疾病的后期阶段,即使吡非尼酮给药减少后,在抑制闭塞性细支气管炎方面仍然非常有效。

这个新发现是非常重要的,其原因有两个:(1)对于不能耐受连续给药的患者,间断性使用吡非尼酮但不影响药物功效,以及(2)TGF-β抑制的时机。因为TGF-β是重要的调节性细胞因子抑制免疫反应,传统的在移植后使用中和TGF-β抗体抑制其活性可能通过促进细胞毒性而产生有害后果,而HSCT后期产生的TGF-β已被发现显著驱动cGVHD。因此,推测移植后期使用吡非尼酮对TGF-β“晚期”抑制,不会影响TGF-β对于细胞毒性的抑制。总体而言,本文提供的数据支持口服吡非尼酮在有潜力作为发生闭塞性细支气管炎的cGVHD患者的1期临床试验药物。

原始出处:
Jing Du et al. Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production. Blood 2017 129:2570-2580; doi: https://doi.org/10.1182/blood-2017-01-758854

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  4. 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  5. 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createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sat May 06 07:20:26 CST 2017, time=2017-05-06, status=1, ipAttribution=)]
    2017-05-07 半夏微凉

    学习了谢谢分享

    0

  6. 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createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sat May 06 07:20:26 CST 2017, time=2017-05-06, status=1, ipAttribution=)]
    2017-05-07 thlabcde

    好东西学习了!

    0

  7. 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createdBy=f503121, createdName=zjubiostat, createdTime=Thu Nov 02 16:14:00 CST 2017, time=2017-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1804887, encodeId=7dd0180488ecc, content=<a href='/topic/show?id=a2ece7762cb' target=_blank style='color:#2F92EE;'>#细支气管#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77762, encryptionId=a2ece7762cb, topicName=细支气管)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e2e0330, createdName=huangdf, createdTime=Mon Jul 17 09:14:00 CST 2017, time=2017-07-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1717599, encodeId=b9691e17599dc, content=<a href='/topic/show?id=dba6e776367' target=_blank style='color:#2F92EE;'>#细支气管炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77763, encryptionId=dba6e776367, topicName=细支气管炎)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=285132431847, createdName=kcb080, createdTime=Thu May 11 16:14:00 CST 2017, time=2017-05-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194967, encodeId=7d1419496eea, content=学习了谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=62, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo5nmIH5IQqCKjJgSCuicPWUWOUcdqt1ROPnEiaOYN4pSHibDv8la3OxNLalvuvUXn8clpJlrpuyTpckgt9OPkeSSdT/0, createdBy=8fd71930726, createdName=半夏微凉, createdTime=Sun May 07 10:55:04 CST 2017, time=2017-05-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194888, encodeId=6ddb19488894, content=好东西学习了!, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92191944782, createdName=thlabcde, createdTime=Sun May 07 08:13:04 CST 2017, time=2017-05-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194750, encodeId=0b49194e504a, content=学习过了,分享分享!, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160914/IMG57D82E721DB581755.jpg, createdBy=4fc81933929, createdName=明天会更好!, createdTime=Sun May 07 01:17:26 CST 2017, time=2017-05-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194535, encodeId=59e61945352c, content=希望能发掘其更大的潜力, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=eff51996281, createdName=1e1b8538m79(暂无匿称), createdTime=Sat May 06 10:39:39 CST 2017, time=2017-05-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194516, encodeId=b7ef194516b4, content=谢谢分享很前沿的资料, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKe6JIArctUjibbaEn6NUN1ib6aTJzVBeoOauj5VGppSU08TUic40qrrxVFCkEhWkCZLfajqxZtMUoSQ/0, createdBy=93b52023248, createdName=杏峰, createdTime=Sat May 06 10:07:34 CST 2017, time=2017-05-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194419, encodeId=575f19441997, content=谢谢分享,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=17, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sat May 06 07:20:26 CST 2017, time=2017-05-06, status=1, ipAttribution=)]
    2017-05-07 明天会更好!

    学习过了,分享分享!

    0

  8. [GetPortalCommentsPageByObjectIdResponse(id=1636391, encodeId=95bf1636391ac, content=<a href='/topic/show?id=ab5b3918830' target=_blank style='color:#2F92EE;'>#吡非尼酮#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=39188, encryptionId=ab5b3918830, topicName=吡非尼酮)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8aba22623857, createdName=1249898am22暂无昵称, createdTime=Mon Jan 15 15:14:00 CST 2018, time=2018-01-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1892079, encodeId=39f618920e9c4, content=<a href='/topic/show?id=1b445e1232d' target=_blank style='color:#2F92EE;'>#支气管#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=57123, encryptionId=1b445e1232d, topicName=支气管)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f503121, createdName=zjubiostat, createdTime=Thu Nov 02 16:14:00 CST 2017, time=2017-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1804887, encodeId=7dd0180488ecc, content=<a href='/topic/show?id=a2ece7762cb' target=_blank style='color:#2F92EE;'>#细支气管#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77762, encryptionId=a2ece7762cb, topicName=细支气管)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e2e0330, createdName=huangdf, createdTime=Mon Jul 17 09:14:00 CST 2017, time=2017-07-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1717599, encodeId=b9691e17599dc, content=<a href='/topic/show?id=dba6e776367' target=_blank style='color:#2F92EE;'>#细支气管炎#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, 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topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92191944782, createdName=thlabcde, createdTime=Sun May 07 08:13:04 CST 2017, time=2017-05-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194750, encodeId=0b49194e504a, content=学习过了,分享分享!, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160914/IMG57D82E721DB581755.jpg, createdBy=4fc81933929, createdName=明天会更好!, createdTime=Sun May 07 01:17:26 CST 2017, time=2017-05-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194535, encodeId=59e61945352c, content=希望能发掘其更大的潜力, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=eff51996281, createdName=1e1b8538m79(暂无匿称), createdTime=Sat May 06 10:39:39 CST 2017, time=2017-05-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194516, encodeId=b7ef194516b4, content=谢谢分享很前沿的资料, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKe6JIArctUjibbaEn6NUN1ib6aTJzVBeoOauj5VGppSU08TUic40qrrxVFCkEhWkCZLfajqxZtMUoSQ/0, createdBy=93b52023248, createdName=杏峰, createdTime=Sat May 06 10:07:34 CST 2017, time=2017-05-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194419, encodeId=575f19441997, content=谢谢分享,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=17, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sat May 06 07:20:26 CST 2017, time=2017-05-06, status=1, ipAttribution=)]
    2017-05-06 1e1b8538m79(暂无匿称)

    希望能发掘其更大的潜力

    0

  9. [GetPortalCommentsPageByObjectIdResponse(id=1636391, encodeId=95bf1636391ac, content=<a href='/topic/show?id=ab5b3918830' target=_blank style='color:#2F92EE;'>#吡非尼酮#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=39188, encryptionId=ab5b3918830, topicName=吡非尼酮)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8aba22623857, createdName=1249898am22暂无昵称, createdTime=Mon Jan 15 15:14:00 CST 2018, time=2018-01-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1892079, encodeId=39f618920e9c4, content=<a href='/topic/show?id=1b445e1232d' target=_blank style='color:#2F92EE;'>#支气管#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=57123, encryptionId=1b445e1232d, topicName=支气管)], attachment=null, authenticateStatus=null, createdAvatar=, 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topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92191944782, createdName=thlabcde, createdTime=Sun May 07 08:13:04 CST 2017, time=2017-05-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194750, encodeId=0b49194e504a, content=学习过了,分享分享!, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160914/IMG57D82E721DB581755.jpg, createdBy=4fc81933929, createdName=明天会更好!, createdTime=Sun May 07 01:17:26 CST 2017, time=2017-05-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194535, encodeId=59e61945352c, content=希望能发掘其更大的潜力, beContent=null, objectType=article, channel=null, level=null, likeNumber=53, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=eff51996281, createdName=1e1b8538m79(暂无匿称), createdTime=Sat May 06 10:39:39 CST 2017, time=2017-05-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194516, encodeId=b7ef194516b4, content=谢谢分享很前沿的资料, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKe6JIArctUjibbaEn6NUN1ib6aTJzVBeoOauj5VGppSU08TUic40qrrxVFCkEhWkCZLfajqxZtMUoSQ/0, createdBy=93b52023248, createdName=杏峰, createdTime=Sat May 06 10:07:34 CST 2017, time=2017-05-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=194419, encodeId=575f19441997, content=谢谢分享,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=17, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sat May 06 07:20:26 CST 2017, time=2017-05-06, status=1, ipAttribution=)]
    2017-05-06 杏峰

    谢谢分享很前沿的资料

    0

  10. 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    2017-05-06 明月清辉

    谢谢分享,学习了

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