Chaudhry Mohammed S, Velardi Enrico, Dudakov Jarrod A, van den Brink Marcel R M
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Immunol Rev. 2016 May;271(1):56-71. doi: 10.1111/imr.12418.
As the primary site of T-cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. As the importance of the role of the thymus has grown, so too has the understanding that it is extremely sensitive to both acute and chronic injury. The thymus undergoes rapid degeneration following a range of toxic insults, and also involutes as part of the aging process, albeit at a faster rate than many other tissues. The thymus is, however, capable of regenerating, restoring its function to a degree. Potential mechanisms for this endogenous thymic regeneration include keratinocyte growth factor (KGF) signaling, and a more recently described pathway in which innate lymphoid cells produce interleukin-22 (IL-22) in response to loss of double positive thymocytes and upregulation of IL-23 by dendritic cells. Endogenous repair is unable to fully restore the thymus, particularly in the aged population, and this paves the way toward the need for exogenous strategies to help regenerate or even replace thymic function. Therapies currently in clinical trials include KGF, use of the cytokines IL-7 and IL-22, and hormonal modulation including growth hormone administration and sex steroid inhibition. Further novel strategies are emerging in the preclinical setting, including the use of precursor T cells and thymus bioengineering. The use of such strategies offers hope that for many patients, the next regeneration of their thymus is a step closer.
作为T细胞发育的主要场所，胸腺在产生强大而又自我耐受的适应性免疫反应中发挥着关键作用，这在面对病原体或肿瘤形成的潜在威胁时至关重要。随着胸腺作用的重要性日益凸显，人们也愈发认识到它对急性和慢性损伤都极为敏感。胸腺在遭受一系列毒性损伤后会迅速退化，并且在衰老过程中也会发生萎缩，尽管其萎缩速度比许多其他组织更快。然而，胸腺具有再生能力，能在一定程度上恢复其功能。这种内源性胸腺再生的潜在机制包括角质形成细胞生长因子（KGF）信号传导，以及最近描述的一种途径，即先天性淋巴细胞在双阳性胸腺细胞缺失和树突状细胞上调IL-23的情况下产生白细胞介素-22（IL-22）。内源性修复无法完全恢复胸腺功能，尤其是在老年人群中，这就为需要外源性策略来帮助再生甚至替代胸腺功能铺平了道路。目前正在进行临床试验的疗法包括KGF、细胞因子IL-7和IL-22的使用，以及激素调节，包括生长激素给药和性类固醇抑制。临床前研究中正在出现进一步的新策略，包括使用前体T细胞和胸腺生物工程。这些策略的应用给许多患者带来了希望，使他们的胸腺再次再生又近了一步。
