A humanized Mouse Model of Beta-islet Cell Autoimmunity

β-胰岛细胞自身免疫的人源化小鼠模型

基本信息

  • 批准号:
    7385117
  • 负责人:
  • 金额:
    $ 30.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-04-01 至 2011-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): A humanized mouse model of b-islet cell autoimmunity. The goal of this proposal is to produce a mouse model on a diabetes permissive murine background with a humanized CD4 T cell compartment, in which to study different approaches towards controlling b-islet cell specific autoimmunity. Due to significant differences in the chaperone function of the murine and human invariant (li) species, the HLA class II transgenic mice, are also being supplied with a human li transgene (hu-li) and a gene knock out for the murine li. Since neither of the two murine Proinsulin (P-lns) varieties (P- Ins1 or P-lns2) contain the major (C-peptide/A-chain) CD4 T cell epitope previously identified in both HLA- DR*0401 transgenic mice and HLA-DR*0401 positive T1D patients, a correctly expressed human preproinsulin transgene (hu-PPI) is also being added. Existing immuno-competent HLA-DR*0401, DQ8, hu- CD4, Ab-/-, NOD mice are being crossed with new humanized li and P-lns transgenic NOD mice. In order to examine the effects of humanizing the li and the Preproinsulin species, the humanized mice, in which human Proinsulin is now a self-protein, will be used to study T cell receptor repertoires and cytokine responses after immunization with human P-lns. We believe that these mice could be key players in pre-testing new islet specific vector based immuno-therapies in T1D. The proposal outlines how to obtain a similarly humanized immuno-deficient mouse model on a NOD background also carrying the Rag-/-, gc-/- double knock out, in which to study the development, maturation, and distribution of a functional immune system after transfer of histo-compatible green fluorescent protein (GFP) labeled murine HSC. These mice will also be ideal recipients for adoptive transfer of GFP labeled potentially autoreactive CD4 & CDS T cell populations triggering disease in the humanized mouse model of T1D. Finally, the proposal suggests to use the immuno- deficient version of the humanized mouse model to examine the different conditions for induction of active immunity versus tolerance in "vaccination studies", where human Proinsulin producing dendritic cells (DC) will be co-transferred with different CD4 and/or CDS T cell populations into histocompatible mice carrying the diabetes susceptible HLA-DR*0401, DOS alleles, a humanized li species, as well as, a correctly expressed human P-lns transgene.
描述(由申请人提供):b岛细胞自身免疫的人源化小鼠模型。本研究的目的是建立具有人源化CD4 T细胞区室的糖尿病小鼠模型,研究控制b岛细胞特异性自身免疫的不同方法。由于小鼠和人类不变性(li)物种在伴侣功能上的显著差异,HLA II类转基因小鼠也被提供了人类li转基因(hu-li)和小鼠li基因敲除。由于两种小鼠胰岛素原(P-lns)品种(P- Ins1或P-lns2)都不包含先前在HLA-DR*0401转基因小鼠和HLA-DR*0401阳性T1D患者中发现的主要(c肽/ a链)CD4 T细胞表位,因此也添加了正确表达的人胰岛素原原转基因(hu-PPI)。现有的具有免疫活性的HLA-DR*0401、DQ8、hu- CD4、Ab-/-、NOD小鼠正在与新的人源化li和P-lns转基因NOD小鼠杂交。为了检验人源化li和prepro胰岛素的影响,将利用人源化的小鼠(其中人pro胰岛素现在是一种自身蛋白)来研究人P-lns免疫后T细胞受体谱和细胞因子反应。我们认为这些小鼠可能是T1D中基于胰岛特异性载体的新免疫疗法预测试的关键参与者。该提案概述了如何在NOD背景下获得类似的人源化免疫缺陷小鼠模型,同样携带Rag-/-, gc-/-双敲除,以研究组织相容性绿色荧光蛋白(GFP)标记的小鼠HSC转移后功能免疫系统的发育,成熟和分布。在人源化T1D小鼠模型中,这些小鼠也将是GFP标记的潜在自身反应性CD4和CDS T细胞群过继转移的理想受体。最后,该建议建议使用免疫缺陷版本的人源化小鼠模型来检验在“疫苗接种研究”中诱导主动免疫与耐受的不同条件,其中人类产生胰岛素原的树突状细胞(DC)将与不同的CD4和/或CDS T细胞群共同转移到携带糖尿病易感HLA-DR*0401, DOS等位基因,人源化li物种,以及组织相容性小鼠。正确表达的人类P-lns转基因。

项目成果

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GRETE SONDERSTRUP其他文献

GRETE SONDERSTRUP的其他文献

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{{ truncateString('GRETE SONDERSTRUP', 18)}}的其他基金

Humanized Transgenic Mice Reproduce the Disease Evolution in Severe RA
人源化转基因小鼠重现严重 RA 的疾病演变
  • 批准号:
    7564889
  • 财政年份:
    2009
  • 资助金额:
    $ 30.92万
  • 项目类别:
Humanized Transgenic Mice Reproduce the Disease Evolution in Severe RA
人源化转基因小鼠重现严重 RA 的疾病演变
  • 批准号:
    7911715
  • 财政年份:
    2009
  • 资助金额:
    $ 30.92万
  • 项目类别:
A Humanized mouse model of B-islet cell autoimmunity
B胰岛细胞自身免疫的人源化小鼠模型
  • 批准号:
    7106046
  • 财政年份:
    2006
  • 资助金额:
    $ 30.92万
  • 项目类别:
A Humanized mouse model of Beta-islet cell autoimmunity
β-胰岛细胞自身免疫的人源化小鼠模型
  • 批准号:
    7216672
  • 财政年份:
    2006
  • 资助金额:
    $ 30.92万
  • 项目类别:
A Humanized Mouse Model of B-islet Cell Autoimmunity
B 胰岛细胞自身免疫的人源化小鼠模型
  • 批准号:
    7623861
  • 财政年份:
    2006
  • 资助金额:
    $ 30.92万
  • 项目类别:
Dominant CD4+ T Cell Regulation Causes Chronic Infection
CD4 T 细胞的主导调节导致慢性感染
  • 批准号:
    6747745
  • 财政年份:
    2001
  • 资助金额:
    $ 30.92万
  • 项目类别:
Dominant CD4+ T Cell Regulation Causes Chronic Infection
CD4 T 细胞的主导调节导致慢性感染
  • 批准号:
    6612932
  • 财政年份:
    2001
  • 资助金额:
    $ 30.92万
  • 项目类别:
Dominant CD4+ T Cell Regulation Causes Chronic Infection
CD4 T 细胞的主导调节导致慢性感染
  • 批准号:
    6511332
  • 财政年份:
    2001
  • 资助金额:
    $ 30.92万
  • 项目类别:
Dominant CD4+ T Cell Regulation Causes Chronic Infection
CD4 T 细胞的主导调节导致慢性感染
  • 批准号:
    6318225
  • 财政年份:
    2001
  • 资助金额:
    $ 30.92万
  • 项目类别:
AUTOIMMUNE T AND B CELL RESPONSES IN TYPE 1 DIABETES
1 型糖尿病中的自身免疫 T 细胞和 B 细胞反应
  • 批准号:
    2766727
  • 财政年份:
    1998
  • 资助金额:
    $ 30.92万
  • 项目类别:

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