自然杀伤T细胞在老年性肝再生中的作用以及白细胞介素22的潜在治疗价值

The loss of regenerative capacity is the most dramatic age-related change in the aging liver. Improving liver regeneration presents a potential therapeutic target in old patients with liver diseases. Our previous work shows that activation of natural killer T (NKT) cells inhibits liver regeneration. Our recent findings demonstrate that interleukin 22(IL-22) is a key cytokine for accelerating liver regeneration in young mice with or without pre-damaged condition. However, the number and function changing of NKT cells in aging liver，effects of NKT cells on aging liver regeneration; and whether IL-22 can promote aging liver regeneration remain obscure. To characterize the role of NKT cells in aging liver regeneration and test the promotion effects of IL-22 on reduced aging hepatocyte proliferation. Partial hepatectomy (PHx) will be used to study liver regeneration. alpha-GalCer, a specific ligand for NKT cells, was used to induce NKT cell activation. The effects of NKT cells and IL-22 on aging liver regeneration will be assessed using different knockout and aged mice. The number and function of NKT cells will be determined by FACS method during aging in human and mice. Taken together, the current project will be important to characterize the role of NKT cells in the reduced aging liver regeneration and to determine if treatment with exogenous IL-22 or up-regulation of this proteins in vivo that can be used to stimulate liver regeneration under aging conditions. This objective may provide some evidence to developing a new safe IL-22 therapeutic strategy in aging liver diseases.

肝再生能力的丧失是老年性病理改变中最为显著的肝脏变化，提高肝脏的再生能力对老年肝病患者具有很好的治疗价值。前期发现激活自然杀伤T（NKT）细胞后可明显抑制2/3肝切除手术（PHx）导致的肝再生；另外还发现白细胞介素（IL-22）可促进原有或无肝疾患年轻小鼠的肝再生能力。然而NKT细胞在老年肝脏中数目功能改变、NKT对老年性肝再生的影响和IL-22是否可以促进老年性肝再生作用仍不甚明了。本课题拟采用经典的PHx模型、α-半乳糖神经酰胺特异性激活NKT细胞和NKT细胞基因敲除小鼠，研究NKT细胞在老年性肝再生中的作用；利用健康年轻人和老年人血液样本，检测NKT细胞数目、功能和IL-22水平差异；应用老年小鼠研究给予IL-22后是否能促进低下的老年性肝再生能力。本课题试图阐明NKT细胞在老年肝和老年性肝再生中的角色，为寻找新的安全的可能应用于治疗老年性肝病导致的肝再生能力不足的药物奠定基础。

肝再生能力的丧失是老年性病理改变中最为显著的肝脏变化，提高肝脏的再生能力对老年肝病患者具有很好的治疗价值。前期发现激活自然杀伤T（NKT）细胞后可明显抑制2/3肝切除手术（PHx）导致的肝再生；老年小鼠对-GalCer诱导的肝损伤更为敏感。老年小鼠对酒精性肝损伤和肝纤维化更为敏感，但这一效应与NKT细胞关系不大。另外我们还发现重组融合IL-22蛋白（IL-22-FP）对有基础肝损伤状态下的肝脏具有促进再生和肝保护作用。IL-22-FP能够有效减轻ConA诱导的小鼠肝组织损伤，促进ConA模型小鼠PHx后的肝再生，其机制可能与激活的p-STAT3及诱导的PCNA、CyclinD1蛋白的表达有关。IL-22-FP能够显著减轻CCl4导致的肝损伤，促进CCl4模型小鼠PHx术后的肝再生。IL-22FP能够有效保护肝脏，显著减轻肝脏缺血再灌注损伤。这些发现提示IL-22FP可用于肝脏疾患状态下促进肝再生的治疗。