Adaptation of NK cell function in ATM deficiency

ATM 缺陷中 NK 细胞功能的适应

• 批准号: 426635836
• 负责人: Professor Dr. Alexander Luis Steinle
• 金额: --
• 依托单位: Labor Zelluläre Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/426635836?language=en
• 关键词: Adaptation; NK; cell; function; ATM

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.

共济失调性毛细血管扩张症（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性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，患者还患有严重且通常危及生命的肺部疾病和造血系统恶性肿瘤。目前的治疗只能轻微缓解疾病症状，没有治愈性治疗。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缺陷中的功能和可能的治疗益处。一个主要的目的是集中在分析的成熟，反应性和NK细胞在小鼠和人类的ATM遗传缺陷的功能适应。我们试图阐明ATM缺陷对NK细胞适应性和NK细胞介导的癌症免疫监视的影响。其次，我们想探讨在Atm缺陷小鼠中同种异体干细胞移植（allo-SCT）的背景下过继转移NK细胞的治疗益处。离体细胞因子激活和过继转移的NK细胞不仅可以增强ATM缺乏症中的NK细胞免疫力，而且还可能改善allo-SCT后的移植和免疫重建。这种策略可能是特别有趣的A-T患者是高度敏感的放射治疗，因此需要替代方法的条件。