Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging
Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging
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DOI：
10.1182/blood-2006-08-043794
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发表时间：
2007-03-15
期刊：
影响因子：
20.3
通讯作者：
Weinberg, Kenneth I.
中科院分区：
文献类型：
--
作者：
Min, Dullei;Panoskaltsis-Mortari, Angela;Weinberg, Kenneth I.
胸腺相关的胸腺功能不全被认为与淋巴造血祖细胞或胸腺微环境的缺陷有关。在这项研究中，我们研究了角质细胞生长因子（KGF），上皮细胞特异性生长因子，是否可以增加老年小鼠胸腺上皮细胞（TECs）的功能恢复的胸腺造血能力。与安慰剂治疗的小鼠相比，KGF治疗的老年小鼠的胸腺细胞结构增加了约4倍，导致与年轻小鼠相同的胸腺细胞结构。KGF单疗程治疗后，增强的胸腺抑制作用可维持约2个月，KGF每月疗程治疗可持续改善。随着KGF治疗后胸腺生成的增强，老年小鼠外周中幼稚CD 4 T细胞的数量和T细胞依赖性抗体的产生得到改善。KGF诱导TEC数量增加，胸腺内白细胞介素-7（IL-7）产生增加，皮质和髓质结构重组。此外，KGF增强了klotho（kl/kl）小鼠的胸腺生成和TEC组织正常化，klotho（kl/kl）小鼠是一种过早变性和衰老的模型，表现出胸腺生成缺陷。结果提示，TEC损伤在胸腺衰老中具有重要的病理生理意义，KGF治疗可能对改善老年人的胸腺生成和免疫功能具有临床意义。
Age-related thymopoletic insufficiency has been proposed to be related to either defects in lymphohematopoietic progenitors or the thymic microenvironment. In this study, we examined whether keratinocyte growth factor (KGF), an epithelial cell-specific growth factor, could increase thymopoietic capacity in aged mice by restoration of the function of thymic epithelial cells (TECs). The thymic cellularity in KGF-treated aged mice increased about 4-fold compared to placebo-treated mice, resulting in an equivalent thymic cellularity to young mice. Enhanced thymopolesis was maintained for about 2 months after a single course of KGF, and sustained improvement was achieved by administration of monthly courses of KGF. With the enhanced thymopolesis after KGF treatment, the number of naive CD4 T cells in the periphery and T-cell-dependent antibody production improved in aged mice. KGF induced increased numbers of TECs and intrathymic interleukin-7 (IL-7) production and reorganization of cortical and medullary architecture. Furthermore, KGF enhanced thymopoiesis and normalized TEC organization in klotho (kl/kl) mice, a model of premature degeneration and aging, which displays thymopoietic defects. The result suggests that TEC damage is pathophysiologically important in thymic aging, and KGF therapy may be clinically useful in improving thymopoiesis and immune function in the elderly.