Immunorejuvenation in the elderly
Immunorejuvenation in the elderly
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DOI：
10.1089/rej.2006.9.111
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发表时间：
2006-03-01
影响因子：
2.6
通讯作者：
Wikby, A
中科院分区：
文献类型：
--
作者：
Pawelec, G;Koch, S;Wikby, A
失调的t细胞介导的免疫在很大程度上增加了老年人对传染病，甚至可能是癌症的易感性。人类这种“免疫衰老”状态的一个标志是大克隆外周T细胞占主导地位，抗原受体异质性有限，T细胞抗原识别库的多样性相应减少。令人惊讶的是，人类克隆扩增的主要驱动力是细胞阴性病毒。由这种持续激活病毒感染引起的终身慢性抗原应激导致特异性CD8 T细胞的克隆衰竭，并且它们在许多方面获得类似的能量和细胞凋亡抵抗状态，并且作者认为出于类似的原因，在癌症患者的肿瘤特异性T细胞中常见。这种过度的功能失调细胞通过填充“免疫空间”和缩小t细胞库以获取新抗原而间接产生免疫抑制作用，也通过细胞因子分泌直接产生抑制作用。在对老年人的纵向研究中，它与预测2年和4年死亡率的“免疫风险概况”有关。因此，我们假设，删除这些功能障碍细胞的积累将对个体有益。通过某些表面分子的表达，有可能区分功能性cmv特异性细胞（对维持免疫监视至关重要）和功能失调细胞。这与旨在使胸腺恢复活力的方法（例如，使用白细胞介素7）以及通过药物和免疫治疗干预针对巨细胞病毒的方法相结合，可能导致一定程度的“免疫恢复”，足以使老年人脱离危险类别，从而延长健康寿命。
Dysregulated T-cell-mediated immunity contributes materially to the increased susceptibility to infectious disease, and possibly cancer, in the elderly. One hallmark of this state of "immunosenescence" in humans is the predominance of large clones of peripheral T cells with limited antigen receptor heterogeneity and a corresponding contraction of diversity in the T-cell antigen recognition repertoire. Surprisingly, a major driving force for these clonal expansions in humans is cytornegalovirus. The lifelong chronic antigenic stress caused by infection with this persistent activating virus results in clonal exhaustion of specific CD8 T cells, and their acquisition of a state of anergy and apoptosis resistance similar in many respects, and, the authors believe for similar reasons, to that commonly seen in the tumor-specific T cells of cancer patients. This excess of dysfunctional cells is indirectly immunosuppressive by filling the "immunologic space" and shrinking the T-cell repertoire for new antigens, as well as directly suppressive via cytokine secretion. It is associated with the "immunologic risk profile" predicting 2- and 4-year mortality in longitudinal studies of very old people. Therefore, it is hypothesized that deletion of such accumulations of dysfunctional cells would be beneficial to the individual. It may be possible to distinguish functional CMV-specific cells (which are essential to maintain immunosurveillance) from dysfunctional ones by their expression of certain surface molecules. This, coupled with methods directed at reinvigorating the thymus (e.g., use of interleukin 7), and targeting CMV by pharmacologic and immunotherapeutic interventions might result in a degree of "immunorejuvenation" sufficient to take elderly individuals out of the risk category and thereby extend healthy longevity.