Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy.
Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy.
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DOI：
10.1038/s41598-021-02572-w
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发表时间：
2021-12-01
影响因子：
4.6
通讯作者：
Gaspar HB
中科院分区：
文献类型：
--
作者：
Moretti FA;Giardino G;Attenborough TCH;Gkazi AS;Margetts BK;la Marca G;Fairbanks L;Crompton T;Gaspar HB
腺苷脱氨酶(ADA，EC3.5.4.4)是嘌呤挽救途径中固有的一种看家酶，它的缺失会导致人类和小鼠严重的联合免疫缺陷(SCID)。缺乏ADA会导致有毒代谢物在细胞内积聚，从而影响T细胞的发育和功能。虽然未经治疗的ADA-SCID是一种致命的疾病，但有不同的治疗方案可用于恢复ADA活性和重建功能正常的免疫系统，包括酶替代疗法(ERT)。事实证明，聚乙二醇化牛ADA(PEG-ADA)形式的ERT对ADA-SCID患者是一种挽救生命的非根治疗法。然而，在许多接受PEG-ADA治疗的患者中，T细胞和B细胞数量较低，免疫恢复情况不佳。在这里，我们显示了ADA-SCID小鼠的胸腺细胞减少，尽管每周一次的聚乙二醇腺苷治疗。这与胸腺缺乏有效的腺苷(ADO)解毒作用有关。我们还发现，在ADA缺乏的胸腺中，胸腺细胞的发育受阻于从dn3到dn4的过渡阶段，胸腺细胞经历了dATP诱导的凋亡，而不是TCRDNA重排或β选择缺陷。我们的研究在详细的水平上证明，每周一次的外源性酶替代并不能完全纠正与ADA缺乏相关的胸腺内代谢或免疫异常。
Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency.
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