ENZYMOLYSIS OF IMMUNE COMPLEXES IN VIVO

体内免疫复合物的酶解

基本信息

批准号：
2066219
负责人：
STEVEN N EMANCIPATOR
金额：
$ 20.64万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-30 至 1995-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2066219
关键词：
clinical chemistry disease /disorder model endopeptidases enzyme mechanism enzyme therapy glomerular filtration rate glomerulonephritis glomerulosclerosis histopathology immune complex immune complex diseases inflammation laboratory rat proteinuria proteolysis renal glomerulus

项目摘要

DESCRIPTION (Adapted from Applicant's Abstract): Glomerulonephritis (GN), an important human disease thought to result from immune complexes (IC) formed or deposited in glomeruli, is associated with significant morbidity and hemodialysis expense. Currently, therapy is limited in both efficacy and options. It is hypothesized that diminishing the glomerular content of the inciting IC should be beneficial and could break a vicious cycle in which immune injury enhances IC deposition resulting in more damage. Applicant's recent publications and other preliminary data show that proteolytic enzymes given systemically to mice and rats do reduce IC deposited in glomeruli and can prevent and reverse proteinuria in acute animal models of GN, and that targeting therapeutic enzymes to the sites where IC lodge improves efficacy. He now seeks to focus on the effects of enzyme therapy on the long term course of experimental GN. He will maintain rats with a model of GN for up to two years with periodic antigen re-challenge to keep the rats nephrotic, and study two distinct mouse models which also progress to sclerosis. Enzyme-treated rats or mice will be compared to controls to determine if treatment can prevent or diminish progression to end stage kidney. Glomerular filtration rate and glomerular scarring will be the criteria to assess progression, and will be compared by multivariate nonparametric analysis. He will examine chronic toxicity by light and gross morphologic examination of tissues, and by measuring release of intracellular enzymes into the plasma. He will also assess renal, liver and lung function by measuring urine concentrating ability, bile concentration in serum, stool fat content and oxygen and carbon dioxide tension in arterial blood. A second goal is to determine the extent to which active enzymes, as opposed to inactive enzymes, digest immune complexes deposited in the kidneys versus those in the circulation, and attempt to elucidate if any other mechanisms exist whereby proteases ameliorate GN. A third set of experiments will measure selected mediators of inflammation, known to be increased in a model immune complex glomerulonephritis to be studied, and determine if the production of these mediators, in the chronic phase, is influenced by enzyme therapy. In addition, he will correlate production of each mediator with glomerulosclerosis and glomerular filtration rate, to determine if any of the mediators is likely associated with progressive glomerular injury. The fourth goal is to extend the principle of enzymatic hydrolyis of immune complexes to a model of glomerulonephritis with nucleic acids implicated as antigens.

描述（改编自申请人的摘要）：肾小球肾炎（GN），一种重要的人类疾病，被认为是由免疫复合物 (IC) 引起的在肾小球中形成或沉积，与显着的发病率相关和血液透析费用。目前，治疗在两种功效上都受到限制和选项。据推测，肾小球含量减少激励 IC 的使用应该是有益的，并且可以打破恶性循环免疫损伤会增强 IC 沉积，导致更多损伤。申请人最近发表的出版物和其他初步数据表明给小鼠和大鼠全身注射蛋白水解酶确实可以降低 IC 沉积在肾小球中，可以预防和逆转急性蛋白尿 GN 动物模型，以及针对该位点的治疗酶 IC 寄存处可提高功效。他现在寻求关注的影响酶疗法对实验性 GN 长期病程的影响。他会使用周期性抗原维持 GN 模型大鼠长达两年重新挑战以保持大鼠肾病，并研究两种不同的小鼠也进展为硬化的模型。经过酶处理的大鼠或小鼠会与对照进行比较以确定治疗是否可以预防或减轻进展至终末期肾。肾小球滤过率和肾小球疤痕将成为评估进展的标准，并将通过多变量非参数分析进行比较。他会检查通过组织的光学和大体形态学检查发现慢性毒性，并通过测量细胞内酶释放到血浆中。他还将通过测量尿液来评估肾、肝和肺功能集中能力、血清胆汁浓度、粪便脂肪含量和动脉血中的氧气和二氧化碳张力。第二个目标是确定活性酶相对于非活性酶的程度酶，消化沉积在肾脏中的免疫复合物与那些在肾脏中的免疫复合物循环，并尝试阐明是否存在任何其他机制蛋白酶可改善 GN。第三组实验将测量选定的炎症介质，已知在模型中增加要研究免疫复合物肾小球肾炎，并确定是否在慢性阶段，这些介质的产生受到以下因素的影响：酶疗法。此外，他还将关联每个产品的生产介导肾小球硬化和肾小球滤过率，确定是否有任何中介因素可能与进行性相关肾小球损伤。第四个目标是扩展原则免疫复合物酶促水解肾小球肾炎模型与作为抗原有关的核酸。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The glycosylation of IgA produced by murine B cells is altered by Th2 cytokines.

小鼠 B 细胞产生的 IgA 糖基化会被 Th2 细胞因子改变。

DOI：
发表时间：
1997
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Chintalacharuvu,SR;Emancipator,SN
通讯作者：
Emancipator,SN

IgA nephropathy: morphologic expression and pathogenesis.

IgA 肾病：形态表达和发病机制。

DOI：
10.1016/s0272-6386(12)81011-0
发表时间：
1994
期刊：
American journal of kidney diseases : the official journal of the National Kidney Foundation
影响因子：
0
作者：
Emancipator,SN
通讯作者：
Emancipator,SN

Functional consequences of the binding of gliadin to cultured rat mesangial cells: bridging immunoglobulin A to cells and modulation of eicosanoid synthesis and altered cytokine production.

麦醇溶蛋白与培养的大鼠系膜细胞结合的功能后果：将免疫球蛋白 A 与细胞桥接，调节类二十烷酸合成和改变细胞因子的产生。

DOI：
10.1016/s0272-6386(12)80987-5
发表时间：
1994
期刊：
American journal of kidney diseases : the official journal of the National Kidney Foundation
影响因子：
0
作者：
Amore,A;Emancipator,SN;Roccatello,D;Gianoglio,B;Peruzzi,L;Porcellini,MG;Piccoli,G;Coppo,R
通讯作者：
Coppo,R

Rat mesangial cell lysis in vitro is induced by cationic polypeptides.

体外大鼠系膜细胞裂解是由阳离子多肽诱导的。