Adaptation of NK cell function in ATM deficiency

共济失调毛细血管扩张症是一种遗传不稳定综合征，由于编码丝氨酸-苏氨酸激酶的基因突变导致进行性多系统疾病（ATM）。除了神经退行性症状外，患者还患有严重且常常危及生命的肺部疾病和造血恶性肿瘤。目前的治疗只能轻微缓解疾病的症状，没有治愈的治疗方法。我们的拨款提案解决了与功能和自然杀伤（NK）细胞在ATM缺乏症中可能的治疗益处有关的两个主要问题。其中一个主要目的是分析具有ATM遗传缺陷的小鼠和人体内NK细胞的成熟、反应性和功能适应性。我们试图揭示ATM缺乏对NK细胞适应性和NK细胞介导的癌症免疫监视的影响。其次，我们想要探索NK细胞过继性转移在异基因干细胞移植（alloo - sct）的背景下对atm缺陷小鼠的治疗益处。体外细胞因子激活和过继转移NK细胞不仅可以增强atm缺乏症中NK细胞的免疫力，而且可能还可以改善同种异体sct后的植入和免疫重建。这种策略对于对放射治疗高度敏感的A-T患者尤其有趣，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.