Adaptation of NK cell function in ATM deficiency

共济失调毛细血管扩张症(A-T)是一种遗传不稳定综合征，由于编码丝氨酸-苏氨酸激酶共济失调毛细血管扩张症突变(ATM)的基因突变而导致进行性多系统疾病。除了神经退行性症状外，患者还患有严重的、往往危及生命的肺部疾病和血液系统恶性肿瘤。目前的治疗方法只能轻微缓解疾病的症状，而且还没有根治的方法。我们的拨款提案解决了两个主要问题，涉及自然杀伤(NK)细胞在ATM缺乏症中的功能和可能的治疗益处。一个主要的目的是分析在ATM中存在遗传缺陷的小鼠和人的NK细胞的成熟、反应和功能适应。我们试图揭示ATM缺陷对NK细胞适合性和NK细胞介导的癌症免疫监视的影响。其次，我们想要探索在ATM缺陷小鼠的异基因干细胞移植(allo-SCT)的背景下过继转移NK细胞的治疗益处。体外细胞因子激活和过继转移的NK细胞不仅可以增强ATM缺乏症患者的NK细胞免疫功能，还可能促进allo-SCT后的植入和免疫重建。对于对放射治疗高度敏感的A-T患者，这一策略可能特别有趣，因此需要替代的调理方法。

Ataxia telangiectasia (A-T) is a genetic instability syndrome that causes a progressive multisystemic disorder as a consequence of mutations in the gene encoding for the serine-threonine kinase Ataxia Telangiectasia-mutated (ATM). Besides neurodegenerative symptoms, patients are suffering from severe and often life-threatening lung disease and hematopoietic malignancies. Current treatments only slightly alleviate diseases symptoms, and no curative treatment is available. Our grant proposal tackles two major questions relating to the functionality and to the possible therapeutic benefit of Natural Killer (NK) cells in ATM deficiency. One major aim is focused on the analyses of the maturation, responsiveness and functional adaption of NK cells in mice and humans with genetic defects in ATM. We attempt to unravel the impact of ATM deficiency on NK cell fitness and NK cell-mediated cancer immunosurveillance. Secondly, we want to explore the therapeutic benefit of an adoptive transfer of NK cells in the context of allo-stem cell transplantation (allo-SCT) in Atm-deficient mice. Ex vivo cytokine-activated and adoptively transferred NK cells may not only strengthen NK cell immunity in ATM-deficiency, but will likely also improve engraftment and immune reconstitution following allo-SCT. This strategy could be especially interesting in A-T patients that are highly sensitive for radiotherapy and therefore require alternate approaches of conditioning.