IMMUNOLOGICAL TOLERANCE AND AGING

衰老伴随着免疫调节状态的改变，其特征在于 对新抗原的反应性降低， 由于自身耐受性的破坏而产生的自身抗体。 研究从这个 实验室已经表明，获得性免疫耐受性很容易 在老年小鼠中存在革兰氏阴性细菌内毒素的情况下流产。 内毒素对免疫系统的调节是由以下过程协调的： 白细胞介素-1（IL-1）。 IL-1是由单核细胞产生的小蛋白质， 吞噬细胞对包括内毒素在内的各种刺激作出反应。 这 本研究的目的是探讨老年小鼠 对IL-1有高度反应 IL-1在获得性巨噬细胞发生和维持中的作用 对异源血清蛋白的免疫耐受性将在 年轻成年（2个月）、中年（12个月）和老年（24个月）小鼠。 耐受诱导时的急性暴露和慢性暴露 将研究由植入的恒定释放胶囊提供的药物。 在 此外，还将研究耐受性诱导的体外模型。 添加的IL-1的存在和不存在。 老年小鼠已被证明对以下物质的致热效应更敏感： 内毒素和IL-1。 体温过低和过高对 在小鼠脾细胞中诱导耐受和抗体形成 将使用体外系统研究不同年龄的人。 IL-1还协调急性期反应，其特征在于 二价阳离子和蛋白质的血清浓度改变， 循环中性粒细胞的数量。 对急性期的了解很少 以及它的各种成分如何影响 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 循环中性粒细胞将在不同年龄的小鼠中进行研究， 急性或慢性暴露于IL-1。 进一步的实验设计来调查的性质， 与年龄相关的增长的根本变化 对IL-1的反应。 将探讨两种可能的机制。

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.