Long-Term MALT1 Inhibition in Adult Mice Without Severe Systemic Autoimmunity.
Long-Term MALT1 Inhibition in Adult Mice Without Severe Systemic Autoimmunity.
复制标题
在没有严重全身性自身免疫的成年小鼠中的长期MALT 1抑制。
DOI：
10.1016/j.isci.2020.101557
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发表时间：
2020-10-23
期刊：
影响因子：
5.8
通讯作者：
Beyaert R
中科院分区：
文献类型：
--
作者：
Demeyer A;Driege Y;Skordos I;Coudenys J;Lemeire K;Elewaut D;Staal J;Beyaert R
蛋白酶MALT 1是NF-κB信号传导的关键调节因子，也是自身免疫和癌症的新治疗靶点。MALT 1抑制剂的临床前结果支持的最初热情被研究所缓和，研究表明小鼠中的生殖系MALT 1蛋白酶失活导致调节性T细胞减少和由于产生IFN-γ的T细胞扩增而导致的致死性多器官炎症。然而，我们发现，尽管调节性T细胞减少，但从成年开始的长期MALT 1失活与严重的全身炎症无关。相反，产生IL-2、TNF-和IFN-γ的CD 4 + T细胞显著减少。在肺和胃中可检测到三级淋巴结构的有限形成，这不会影响整体健康。我们的数据表明，在产前或成年生活中MALT 1抑制有不同的结果，成年期长期MALT 1抑制与严重的副作用无关。诱导MALT 1失活长达6个月在没有严重毒性的情况下成年小鼠中MALT 1失活降低T淋巴细胞而没有效应T细胞活化长期MALT 1失活导致三级淋巴结构形成产前或成年生活中MALT 1抑制具有不同的结果免疫学;细胞生物学
The protease MALT1 is a key regulator of NF-κB signaling and a novel therapeutic target in autoimmunity and cancer. Initial enthusiasm supported by preclinical results with MALT1 inhibitors was tempered by studies showing that germline MALT1 protease inactivation in mice results in reduced regulatory T cells and lethal multi-organ inflammation due to expansion of IFN-γ-producing T cells. However, we show that long-term MALT1 inactivation, starting in adulthood, is not associated with severe systemic inflammation, despite reduced regulatory T cells. In contrast, IL-2-, TNF-, and IFN-γ-producing CD4+ T cells were strongly reduced. Limited formation of tertiary lymphoid structures was detectable in lungs and stomach, which did not affect overall health. Our data illustrate that MALT1 inhibition in prenatal or adult life has a different outcome and that long-term MALT1 inhibition in adulthood is not associated with severe side effects. Inducible MALT1 inactivation for up to 6 months in the absence of severe toxicity MALT1 inactivation in adult mice decreases Tregs without effector T cell activation Long-term MALT1 inactivation results in tertiary lymphoid structure formation MALT1 inhibition in prenatal or adult life has a different outcome Immunology; Cell Biology
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DOI：
10.1038/nrd2760
发表时间：
2009-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
MALT1自切解对于小鼠的调节T细胞稳态和抗肿瘤免疫至关重要。
影响因子：
5.4
作者：
Baens M;Stirparo R;Lampi Y;Verbeke D;Vandepoel R;Cools J;Marynen P;de Bock CE;Bornschein S
通讯作者：
Bornschein S
影响因子：
4.6
作者：
Hameyer, Dorothe;Loonstra, Ate;Bockamp, Ernesto
通讯作者：
Bockamp, Ernesto
影响因子：
7.3
作者：
Demeyer, Annelies;Skordos, Ioannis;Beyaert, Rudi
通讯作者：
Beyaert, Rudi
影响因子：
8.8
作者：
Gewies, Andreas;Gorka, Oliver;Ruland, Juergen
通讯作者：
Ruland, Juergen