An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice.
An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice.
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DOI：
10.1126/sciimmunol.aba5264
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发表时间：
2020-08-14
影响因子：
24.8
通讯作者：
Gavin MA
中科院分区：
文献类型：
--
作者：
Khoryati L;Pham MN;Sherve M;Kumari S;Cook K;Pearson J;Bogdani M;Campbell DJ;Gavin MA
白细胞介素-2（IL-2）控制调节性T（Treg）细胞的稳态和功能，并且IL-2途径中的缺陷促成多种自身免疫性疾病。尽管重组IL-2疗法在某些炎性病症中是有效的，但IL-2也激活炎性效应子应答的能力突出了对具有改善的Treg细胞特异性的基于IL-2的治疗剂的需要。从一组合理设计的鼠IL-2变体中，我们鉴定了由于对IL-2受体组分CD 25的依赖性增加而具有降低的效力和增强的Treg细胞选择性的IL-2突变蛋白。作为Fc融合的同二聚体，最佳Fc.IL-2突变蛋白诱导选择性Treg细胞富集，并在宽剂量范围内降低效应细胞的激动作用。此外，尽管是较弱的激动剂，但总体Treg细胞生长更大且更持续，这是由于与Fc融合的野生型IL-2相比，Fc.IL-2突变蛋白的受体介导的清除减少。在非肥胖糖尿病（NOD）小鼠胰腺中存在活化的致病性T细胞的情况下也观察到优先Treg细胞富集，尽管在IL-2 R近端应答中Treg细胞选择性丧失。这些特性有助于在不频繁给药的情况下有效和延长NOD糖尿病的消退。CD 25依赖性IL-2突变蛋白扩增调节性T细胞并控制非肥胖糖尿病（NOD）小鼠的自发性糖尿病。
Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (Treg) cells and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved Treg cell-specificity. From a panel of rationally designed murine IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg cell-selectivity due to increased dependence on the IL-2-receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg cell enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg cell growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared to Fc-fused wild-type IL-2. Preferential Treg cell enrichment was also observed in the presence of activated pathogenic T cells in the pancreas of non-obese diabetic (NOD) mice, despite a loss of Treg cell-selectivity in an IL-2R-proximal response. These properties facilitated potent and extended resolution of NOD diabetes with infrequent dosing schedules. A CD25-dependent IL-2 mutein expanded regulatory T cells and controlled spontaneous diabetes in non-obese diabetic (NOD) mice.
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影响因子：
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