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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs
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BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs

机译:BH3模拟物拮抗有限的生存Bcl-2蛋白代表另一类选择性免疫调节药物

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摘要

Death by apoptosis shapes tissue homeostasis. Apoptotic mechanisms are so universal that harnessing them for tailored immune intervention would seem challenging; however, the range and different expression levels of pro- and anti-apoptotic molecules among tissues offer hope that targeting only a subset of such molecules may be therapeutically useful. We examined the effects of the drug ABT-737, a mimetic of the killer BH3 domain of the Bcl-2 family of proteins that induces apoptosis by antagonizing Bcl-2, BcI-X_l, and Bcl-W (but not Mcl-1 and A1), on the mouse immune system. Treatment with ABT-737 reduced the numbers of selected lymphocyte and dendritic cell subpopulations, most markedly in lymph nodes. It inhibited the persistence of memory B cells, the establishment of newly arising bone marrow plasma cells, and the induction of a cytotoxic T cell response. Preexisting plasma cells and germinal centers were unaffected. Notably, ABT-737 was sufficiently immunomodulatory to allow long-term survival of pancreatic allografts, reversing established diabetes in this model. These results provide an insight into the selective mechanisms of immune cell survival and how this selectivity avails a different strategy for immune modulation.
机译:细胞凋亡导致的死亡影响了组织的动态平衡。凋亡机制是如此普遍,以至于利用它们进行量身定制的免疫干预似乎具有挑战性。然而,组织中促凋亡和抗凋亡分子的范围和不同的表达水平提供了希望仅靶向此类分子的子集可能在治疗上有用。我们检查了药物ABT-737的作用,ABT-737是Bcl-2家族杀伤蛋白BH3域的模拟物,可通过拮抗Bcl-2,Bcl-X_1和Bcl-W诱导凋亡(但不是Mcl-1和A1),对小鼠免疫系统。 ABT-737的治疗减少了选定的淋巴细胞和树突状细胞亚群的数量,最明显的是在淋巴结中。它抑制记忆B细胞的持久性,新出现的骨髓浆细胞的建立以及细胞毒性T细胞反应的诱导。先前存在的浆细胞和生发中心不受影响。值得注意的是,ABT-737具有足够的免疫调节作用,可实现胰腺同种异体移植物的长期存活,从而逆转了该模型中已建立的糖尿病。这些结果提供了对免疫细胞存活的选择性机制的了解,以及这种选择性如何为免疫调节提供了不同的策略。

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  • 作者单位

    Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia;

    rnlmmunology Division The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia;

    rnlmmunology Division The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia;

    rnAutoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia;

    rnAutoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia;

    rnMolecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia Department of Microbiology and Immunology, University of Melbourne, Parkville 3010, Australia;

    rnMolecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia;

    rnAutoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia;

    rnlmmunology Division The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    apoptosis; immunity; memory; transplantation;

    机译:细胞凋亡免疫;记忆;移植;

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