ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE

抗肾小球基底膜疾病

• 批准号: 6381304
• 负责人: RAGHU KALLURI
• 金额: $ 17.97万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381304
• 关键词: B lymphocyte; Goodpasture's syndrome; T lymphocyte; autoantibody; basement membrane; collagen; cytokine; disease /disorder model; gene targeting; genetically modified animals; glomerulonephritis; immunopathology; laboratory mouse; laboratory rabbit; laboratory rat; monoclonal antibody; renal glomerulus

DESCRIPTION (Adapted from Investigator's Abstract): Anti-GBM disease in humans is associated with rapidly progressive glomerulonephritis, anti-a3(IV)NC1 collagen antibodies, and sometimes pulmonary hemorrhage. Anti-GBM disease with kidney and lung involvement is typically referred to as Goodpasture syndrome. Although the primary target for autoantibodies from patients with anti-GBM disease has been identified as the a3(IV)NC1 collagen, its role in the immunopathology of this disease has not been investigated. The long term objective of this proposal is to study the pathogenesis of anti-glomerular basement membrane (GBM) disease in mice immunized with a3 chain of type IV collagen. Initially, as part of specific aim 1, the investigators will continue the characterization of murine anti-GBM disease. Their preliminary experiments show that immunization with a3(IV) collagen produces organ specific inflammatory renal disease mimicking human anti-GBM disease in Goodpasture syndrome in genetically susceptible inbred mice. While all inbred strains of mice immunized with the antigen produced IgG1/Th2-like anti-GBM antibodies that cross react with human Goodpasture autoantibodies, only a select few major histocompatibility complex haplotypes (MHC) developed inflammatory disease in organ tissues. Crescentic glomerulonephritis and lung hemorrhage were restricted to MHC haplotypes H-2 s,b, and d that express additional IL-2 and IgG2a/Th1-like responses which map to the Ab/Aa region of H-2s; immune response genes in HLA-DR/DQ correspond to this region in humans predisposed to Goodpasture syndrome. As the second part of this aim, antibodies and immune cells from mice with anti-GBM disease will be passively and adoptively transferred, respectively, into native recipients. The transfer of disease, will evaluate the contribution of various effector mechanisms. Knockout mice deficient in B cells, T cells and cytokines will also be used to further investigate the contributions of these immune cells and cytokines on disease expression. The molecular determinants of the B-lymphocyte response in mice with nephritis will be examined in specific aim 2. In the first part of the second specific aim we will make a3(IV)NC1 collagen-specific monoclonal antibodies from susceptible and non-susceptible mice. The monoclonal antibodies will be tested in passive transfer experiments for their capacity to induce anti-GBM disease. The disease-inducing and/or non-inducing monoclonals will be further studied to identify the antigen-binding epitopes using synthetic peptides derived from the murine a3(IV)NC1 collagen amino acid sequence. A select panel of monoclonals will be used as immunogens in rabbits and rats to in the hopes of identifying a cross-reactive idiotype. The mouse model described in this proposal closely resembles human anti-GBM disease and Goodpasture syndrome in is immunopathology and in the specificity of its polyclonal autoantibody repertoire. Successful completion of this project should provide new experimental information regarding the processes that govern the pathogenesis of human anti-GBM disease.

描述（改编自研究者摘要）： 人类与快速进行性肾小球肾炎有关， 抗α 3（IV）NC 1胶原抗体，有时还有肺出血。 抗GBM疾病与肾脏和肺部的参与，通常是指 肺出血肾炎综合征 虽然自身抗体的主要目标 来自患有抗GBM疾病的患者的已被鉴定为a3（IV）NC 1 胶原蛋白，其在这种疾病的免疫病理学中的作用尚未被研究 研究了 这项建议的长远目标是研究 小鼠抗肾小球基底膜病的发病机制 用IV型胶原α 3链免疫。 首先，作为具体的 目的1，研究人员将继续对小鼠进行表征， 抗GBM疾病。 他们的初步实验表明， a3（IV）胶原蛋白产生器官特异性炎症性肾病， 遗传易感肺出血肾炎综合征中人类抗GBM疾病 近交系小鼠 尽管用抗原免疫的所有近交系小鼠 产生IgG 1/Th 2样抗GBM抗体，其与人GBM交叉反应， Goodpasture自身抗体，仅选择少数主要组织相容性 复杂单倍型（MHC）在器官组织中发展成炎性疾病。 新月体肾炎和肺出血仅限于MHC 单倍型H-2 s、B和d表达额外的IL-2和IgG 2a/Th 1样 映射到H-2s的Ab/Aa区域的免疫应答基因; HLA-DR/DQ对应于易患Goodpasture的人类的该区域 综合征 作为这一目标的第二部分， 将具有抗GBM疾病的小鼠被动地和过继地转移， 分别输入本地接收器。 疾病的传播，将 评估各种效应器机制的贡献。 敲除小鼠 缺乏B细胞、T细胞和细胞因子的细胞也将用于进一步 研究这些免疫细胞和细胞因子对疾病的贡献 表情 小鼠B淋巴细胞反应的分子决定因素 肾炎将在具体目标2中进行检查。 第一部分 第二个具体的目的，我们将使a3（IV）NC 1胶原特异性单克隆抗体 来自易感和非易感小鼠的抗体。 单克隆 将在被动转移实验中测试抗体的能力， 诱发抗GBM疾病 诱发和/或非诱发疾病的 单克隆抗体将进一步研究，以确定抗原结合表位 使用衍生自鼠α 3（IV）NC 1胶原蛋白氨基的合成肽 酸性序列 一组选定的单克隆抗体将用作免疫原， 兔子和老鼠，希望能找出一个交叉反应的独特型。 该提案中描述的小鼠模型与人抗GBM非常相似 疾病和Goodpasture综合征在免疫病理学和 其多克隆自身抗体库的特异性。 成功 该项目的完成应提供新的实验信息 关于控制人类抗GBM发病机制的过程， 疾病

项目成果

BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.

BMP-7 可以抵消 TGF-β1 诱导的上皮间质转化并逆转慢性肾损伤。

• 发表时间: 2003
• 期刊: Nat Med 9
• 作者: Zeisberg M;Hanai J;Sugimoto H;Mammoto T;Charytan D;Strutz F;Kalluri R.
• 通讯作者: Kalluri R.

Antitumor interaction of short-course endostatin and ionizing radiation.

短程内皮抑素和电离辐射的抗肿瘤相互作用。

• 发表时间: 2000
• 期刊: Cancer journal (Sudbury, Mass.)
• 作者: Hanna,NN;Seetharam,S;Mauceri,HJ;Beckett,MA;Jaskowiak,NT;Salloum,RM;Hari,D;Dhanabal,M;Ramchandran,R;Kalluri,R;Sukhatme,VP;Kufe,DW;Weichselbaum,RR
• 通讯作者: Weichselbaum,RR

Characterization of the anti-angiogenic properties of arresten, an alpha1beta1 integrin-dependent collagen-derived tumor suppressor.

• DOI: 10.1016/j.yexcr.2008.08.011
• 发表时间: 2008-11-01
• 期刊: Experimental cell research
• 影响因子: 3.7
• 作者: Nyberg P;Xie L;Sugimoto H;Colorado P;Sund M;Holthaus K;Sudhakar A;Salo T;Kalluri R
• 通讯作者: Kalluri R

NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele.

• DOI: 10.1172/jci16242
• 发表时间: 2002-12
• 期刊: The Journal of clinical investigation
• 作者: H. Tsukaguchi;A. Sudhakar;T. C. Le;Trang-Tiffany Nguyen;Jun Yao;Joshua A. Schwimmer;A. Schachter;E. Poch;P. Abreu;G. Appel;A. B. Pereira;R. Kalluri;M. Pollak

Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease.

• DOI: 10.1371/journal.pmed.0030100
• 发表时间: 2006-04
• 期刊: PLOS MEDICINE
• 影响因子: 15.8
• 作者: Zeisberg, Michael;Khurana, Mona;Rao, Velidi H.;Cosgrove, Dominic;Rougier, Jean-Philippe;Werner, Michelle C.;Shield, Charles F., III;Werb, Zena;Kalluri, Raghu
• 通讯作者: Kalluri, Raghu