IMMUNOLOGICAL TOLERANCE AND AGING

衰老伴随着免疫调节状态的改变，其特征是 对新抗原的反应性降低，并增加新抗原的形成 由于自身耐受性的崩溃而产生自身抗体。从这里开始的研究 实验室已经证明，获得性免疫耐受很容易 在革兰氏阴性细菌内毒素存在的老年小鼠中流产。 内毒素对免疫系统的调节是由 白介素1(IL-1)。IL-1是由单个核细胞产生的一种小分子蛋白质 吞噬细胞对包括内毒素在内的各种刺激做出反应。这 本研究的目的是探讨这样一个命题，即衰老的小鼠 对IL-1有高反应。 IL-1在获得性脑发育和维持中的作用 对一种异种血清蛋白的免疫耐受性将在 青年(2月龄)、中年(12月龄)和老年(24月龄)小鼠。 耐受诱导时的急性暴露和慢性暴露 将对植入恒定释放胶囊所提供的药物进行调查。在……里面 此外，还将研究一种诱导耐受性的体外模型 存在和不存在添加的IL-1。 已有研究表明，衰老的小鼠对热原作用更敏感。 包括内毒素和IL-1。体温过低和过热对机体功能的影响 小鼠脾细胞免疫耐受诱导及抗体形成 不同年龄的人将使用体外系统进行研究。 IL-1还协调急性时相反应，其特征是 血清二价阳离子和蛋白质浓度改变并增加 循环中的中性粒细胞数量。人们对急性呼吸道合并症知之甚少 老化过程中的相态响应及其各种成分如何影响 免疫系统。在目前的研究中，血清淀粉样蛋白A的诱导 蛋白质合成，降低血清铁水平和 将在不同年龄的小鼠身上研究循环中的中性粒细胞 急性或慢性暴露于IL-1。 进一步的实验被设计用来研究 占与年龄相关的增加的根本性变化 对IL-1的反应性。我们将探索两种可能的机制。

Aging is accompanied by an altered immunoregulatory state characterized by reduced responsiveness to neoantigens and increased formation of autoantibodies due to the breakdown of self tolerance. Studies from this laboratory have shown that acquired immunological tolerance is readily aborted in the presence of gram negative bacterial endotoxin in aged mice. Modulation of the immune system by endotoxin is orchestrated by interleukin-1 (IL-1). IL-1 is a small protein produced by mononuclear phagocytes in response to a variety of stimuli including endotoxin. This is the purpose of the present studies to explore the thesis that aged mice are hyperreactive to IL-1. The effects of IL-1 on the development and maintenance of acquired immunological tolerance to a heterologous serum protein will be studied in young adult (2 months), middle aged (12 months) and old (24 months) mice. An acute exposure at the time of tolerance induction and chronic exposure afforded by implanted constant release capsules will be investigated. In addition, an in vitro model of tolerance induction will be studied in the presence and absence of added IL-1. Aged mice have been shown to be more sensitive to the pyrogenic effects of both endotoxin and IL-1. The role of hypo- and hyperthermia on the induction of tolerance and of antibody formation in splenocytes from mice of different ages will be investigated using in vitro systems. IL-1 also orchestrates the acute phase response which is characterized by altered serum concentration of divalent cations and proteins and increased numbers of circulating neutrophils. Very little is known about the acute phase response in aging and how its various components might affect the immune system. In the present studies, the induction of serum amyloid A protein synthesis, reduction of serum levels of iron and levels of circulating neutrophils will be studied in mice of different ages given acute or chronic exposure to IL-1. Further experiments are designed to investigate the nature of the fundamental change which accounts for the age-related increased responsiveness to IL-1. Two possible mechanisms will be explored.