STUDIES OF SOLUBLE IMMUNOREGULATORS IN MURINE LUPUS

NZB小鼠是人类狼疮的第一个实验动物模型。在……里面 以前的研究已经证明了一种特征性的多动症B NZB小鼠早期的淋巴生成。然而，这是一种 暂时性现象，并在出现之前迅速下降 自身免疫现象与自身免疫性疾病的发展。 最近我们发现了一些可以增强SigB的体液因子 正常人Sig B前体细胞的获取和集落形成 体外培养的小鼠品系。它们最早是在VERY的血清中鉴定出来的 幼年NZB小鼠在B淋巴细胞生成活跃时被称为NZB 血清因子(NZB-SF)。小鼠血清NZB-SF活性随增龄而降低 与NZB-SF一度过度活跃的B下降平行，并被指定为 60kd NZB-SF。生物学功能的血清学研究和分析 表明这与明确定义的分子是有区别的 细胞因子。 我们推测，在NZB小鼠中，NZB-SF的过量产生可能是 在一定程度上导致了早产的过度活跃的B淋巴细胞 晚年的自体免疫功能失调。的长期目标是 这项提议是为了检验这一假说，并阐明60 KD NZB-SF与自身免疫的关系眼前的目标是 进一步鉴定60kd NZB-SF并确定其生物学特性 功能。 为此，我们提出了4个具体目标。它们是分子 60kd NZB-SF基因克隆及DNA分析鉴定 60亚基编码基因的克隆、序列及重组蛋白产物 KD NZB-SF，2)60kd NZB-SF的细胞来源鉴定 利用酶联免疫吸附试验、生物检测、免疫细胞化学分析、Northern印迹 分析，可能还有原位杂交技术，3)表征 免疫亲和膜法检测NZB血清中的NZB-SF 层析，4)60kd NZB-SF对B淋巴细胞作用的分析 NZB-SF对非自身免疫品系小鼠的体内给药 另一种方法是给幼龄NZB小鼠注射抗NZB-SF的单抗。

NZB mice are the first experimental animal model of human lupus. In previous studies we have demonstrated a characteristic hyperactive B lymphopoiesis in the early life of the NZB mice. However, this is a temporary phenomenon and declines rapidly prior to the manifestation of autoimmune phenomena and the development of autoimmune disease. Recently we have identified humoral factors which can enhance sIg-B acquisition and colony formation by sIg B precursor cells from normal strains of mice in vitro. They were first identified in the serum of very young NZB mice when they were active in B lymphopoiesis and thus termed NZB serum factors (NZB-SF). The NZB-SF activity in serum decreases with age in parallel to the decline of once hyperactive B of NZB-SF and designated as the 60 kd NZB-SF. Serological studies and analyses of biological functions of this molecule indicate that this is distinguishable from well defined cytokines. We hypothesized that in NZB mice the overproduction of NZB-SF may be, at least in part responsible for the premature hyperactive B lymphopoiesis and the dysregulation autoimmunity in later life. The long term objective of this proposal is to test this hypothesis and elucidate the roles of the 60 kd NZB-SF in relation to autoimmunity. The immediate goals are to characterize the 60 kd NZB-SF further and to define its biological functions. For that purpose, we propose 4 specific aims. They are 1) molecular characterization of 60 kd NZB-SF by cloning genes and analyzing DNA sequence and recombinant protein products of cloned cDNA coding for the 60 kd NZB-SF, 2) identification of cellular origin of the 60 kd NZB-SF utilizing ELISA, bioassays, immunocytochemical analysis, northern blot analysis, and possibly in situ hybridization technique, 3) characterization of NZB-SF present in NZB serum using immunoaffinity membrane chromatography, 4) analyses of effects of 60 kd NZB-SF on B lymphopoiesis in vivo by administration of NZB-SF to mice of non-autoimmune strains or alternatively by administration of mAb against NZB-SF to young NZB mice.