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），由免疫复合物（IC）引起的一个重要人类疾病在肾小球中形成或沉积与明显的发病率有关和血液透析费用。目前，治疗两种功效都受到限制和选项。假设减少肾小球含量煽动IC应该是有益的，可能会破坏恶性循环免疫损伤增强了IC沉积，导致更多损害。申请人最近的出版物和其他初步数据表明全身给小鼠的蛋白水解酶确实减少了IC 沉积在肾小球中，可以预防急性中的蛋白尿 GN的动物模型，以及将治疗酶靶向部位的动物模型 IC Lodge提高功效的地方。他现在试图专注于实验性GN的长期过程中的酶治疗。他会的用GN模型保持大鼠长达两年，并定期抗原重新挑战以保持大鼠肾病，并研究两只不同的小鼠也发展到硬化症的模型。酶处理的大鼠或小鼠将将其与对照组进行比较，以确定治疗是否可以预防或减少进展到末期肾脏。肾小球滤过率和肾小球疤痕将是评估进展的标准，并将通过多元非参数分析进行比较。他会检查慢性毒性通过对组织的光和总形态学检查，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脏，肝脏和肺功能浓缩能力，血清中的胆汁浓度，凳子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与非活性相反的程度酶，沉积在肾脏中的消化免疫复合物与循环，并试图阐明是否存在任何其他机制蛋白酶可以改善GN。第三组实验将测量选定的炎症介质，已知在模型中增加免疫复合肾小球肾炎要研究，并确定是否是否在慢性阶段，这些介体的产生受到酶治疗。此外，他将将每个人的生产相关联肾小球硬化和肾小球过滤率的介体确定任何调解人是否可能与进步有关肾小球损伤。第四个目标是扩展免疫复合物的酶促水解为肾小球肾炎模型核酸与抗原有关。

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。