Signalingand Functional Defects in the Immune Cells of Aged Subjects

几项研究表明，免疫抑制和 癌症患者T细胞信号的变化，以及最近的变化 在其他疾病中，如慢性感染和自身免疫。相似的 在老龄化人口中也观察到了这一发现。我们 认为一个共同的潜在机制(S)可能参与了所有 这些免疫抑制状态。更好地理解 其中涉及的生物学和分子机制(S) 改变可能有助于矫正手法的发展 以克服或逆转这些 免疫缺陷。在长期癌症患者中的研究 以及患有慢性炎症的患者(即 麻风病)表现出各种缺陷。 人T细胞在TCR结扎后的信号通路。更多 具体地说，TCR Zeta链以及NFkB的差异 在这些不同患者来源的T细胞中的表达 观察到的。我们的假设是衰老是一种慢性病， 可能是一种类似的慢性炎症 老年人的免疫功能可能发生改变。 在癌症、艾滋病和麻风病患者身上观察到的。此外, 与癌症患者类似，来自老年患者的T细胞也 表现出T细胞增殖反应减弱以及T细胞功能低下 TCR结扎后的细胞钙和肌醇反应。肿瘤细胞 或参与这些低效免疫的调节性免疫细胞 过程也可能负责释放可溶性因子(S) 这可能导致这些抑制作用。其他研究 揭示了系统性T细胞表型转换的发生 在艾滋病和癌症患者中。有人提议，在 在衰老过程中，Th1样细胞转化为Th2或Th3样细胞 它们被认为是更具抑制性的淋巴细胞 人口。定义各种信号缺陷和T细胞 老式主机内的交换应允许生成 模型可能会干预和改变这种变化。一个主要领域 今年和明年的重点将是NFkB/IKB和T 青年和老年人类T细胞的细胞受体信号通路 长期癌症患者的淋巴细胞中也是如此。 此外，额外的信号分子和通路，如 JAK、STAT和各种共刺激和凋亡分子 还将接受检查。最后，还将进行其他研究 检查不同细胞因子和激素的影响 利用原代T细胞诱导多种TCR信号的改变 和/或T细胞克隆。从癌症患者中提取的各种液体作为 以及由活化的Th1和Th2产生的培养上清 还将检查克隆人是否具有促进信号传递的能力 改装。至于癌症的研究，重点将放在肿瘤上。 与老龄化人口更相关的类型，如结肠癌，卵巢， 前列腺癌、乳腺癌、多发性骨髓瘤、淋巴细胞和B细胞 淋巴瘤。总体而言，需要新的战略来改善 免疫系统根除微小残留物的能力 标准化疗后的疾病(因此治疗失败)。 这与老年患者尤其相关，他们可能患有 不同程度的免疫抑制和/或对 一些有毒的养生法。这些研究有望揭示出准确的 癌症患者和老年人中存在缺陷的分子通路 研究对象。有了这样的认识，我们或许能够扭转 这些免疫变化和提高目前的抗肿瘤作用 战略。

Several studies have shown immunosuppression and alterations in T cell signaling in cancer patients, and more recently in other diseases like chronic infections and autoimmunity. Similiar findings have also been observed in the aging population. We believe a common underlying mechanism(s) may be involved in all of these immunosuppressive conditions. A greater understanding of the biological and molecular mechanism(s) involved in these alterations may aid in the development of a corrective manipulation of the host immune system to overcome or revert these immunological defects. Studies within long term cancer patients as well as patients suffering from chronic inflammation (i.e. Lepromatous Leprosy) have demonstrated various defects in the signaling pathways in human T cells post TCR ligation. More specifically, differences in the TCR zeta chain as well as NFkB expression in T cells derived from these various patients have been observed. Our hypothesis is that aging is a chronic disease and possibly a form of chronic inflammation in that similar immunological alteration may occur in elderly individuals to those that are observed in cancer, AIDS, and leprosy patients. In addition, similar to cancer patients, T cells derived from elderly subjects also exhibit diminished T cell proliferative responses as well as poor T cell calcium and inositol responses post TCR ligation. Tumor cells or regulatory immune cells involved in these inefficient immune processes may also be responsible for releasing soluble factor(s) which may results in these suppressive effects. Additional studies have revealed that a systemic T cell phenotypic switching occurs within AIDS and cancer patients. It has been proposed that, during the aging process, Th1-like cells convert to Th2- or Th3- like cells which are believe to be the more suppressive lymphocyte populations. Defining the various signaling defects and T cell switching within an aged host should permit the generation of models to possibly intervene and alter such changes. A major area of focus this year and in the next year will be the NFkB/IkB and T cell receptor signaling circuits in young and old human T cells as well as in lymphocytes derived from long- term cancer patients. Furthermore, additional signaling molecules and pathways such as JAK, STAT, and various costimulatory and apoptotic molecules will also be examined. Finally, additional studies will be performed examining the effects of various cytokines and hormones at inducing various TCR signaling alterations using primary T cells and/or T cell clones. Various fluids derived from cancer patients as well as culture supernatants derived from activated Th1 and Th2 clones will also be examined for their ability to facilitate signaling alterations. As for the cancer studies, emphasis will be put in tumor types more relevant to the aging population like colon, ovarian, prostate, breast cancers, multiple myeloma, CLL and B- cell lymphomas. Overall, new strategies are needed to improve the ability of the immune system to eradicate the minimal residual disease (therefore treatment failure) after standard chemotherapy. This is especially relevant to older patients whom may have different degrees of immunosuppression and/or less tolerance to some toxic regimens. These studies will hopefully reveal the precise molecular pathways that are defective in cancer patients and elderly subjects. With such an understanding, we may be able to reverse these immune alterations and improve the current anti-tumor strategies.