LOSS OF TH1 IMMUNE FUNCTION IN FIV-INFECTED CATS

感染 5 种猫的 TH1 免疫功能丧失

基本信息

项目摘要

This application is a resubmission of a competitive renewal application on the mechanism(s) of FIV immunopathogenesis leading to the loss of Thl immune functions which is the hallmark of both HIV and FIV AIDS. CD8+, L-selectin-neg, integrin-hi effector/memory cells rapidly replace naive CD8+ cells in the blood of FIV-infected cats, such that 90 percent of the CD8+ cells in blood may be of effector/memory phenotype by late asymptomatic stage. This observation closely mimics those changes in blood of HIV-infected patients. Furthermore, in both FIV and HIV infection, a marked increase in CD4+, L-selectin-neg cells occurs in the circulation during late stages of infection and high proportion of the T cells in the lymph node express effector/memory phenotype. Recently, CD4 T cell loss has been correlated to increased apoptosis of LN and increased state of immune activation in HIV-infected individuals and in nonhuman primate AIDS models. Both CD4+ and CD8+ T cells had increased expression of B7 molecules in the lymph nodes of FIV-infected cats and these cell types increase progressively throughout the course of the disease such that they represent 75-100 percent ofthe LN T cells. However, the upregulation of B7 expressing T cells was minimal in the blood. In many cellular and animal models of immune modulation, B7- 1 (CD80) interaction with CD28 leads to costimulatory activation signal, while B7-2 (CD86) interaction with CTLA4 leads to down-regulation or anergy of such activation signal. Based on above observations, the applicant proposes that the CD4+ T cell loss in AIDS is caused by anergy and apoptosis that develops upon B7-CTLA4 interaction between CD8+B7+ T cells and activated CD4+, CTLA4+ T cells. Studies in specific aim 1 will test their hypothesis, that activated CD8+B7+ cells in lymph node of FIVinfected cats have phenotype and functional characteristics of FIV-suppressor cells. The activated CD8+B7+ cells will be analyzed for T-cell activation markers by FACS, cytokine and chemokine profile by RT-qcPCR, FIV suppressor activity, and CTL activity. In specific aim 2, the applicant will test their hypothesis that there is a high level of lymphocyte apoptosis in the lymph nodes of asymptomatic FIV-infected cats and that the LN CD8+B7+ cells induce anergy and apoptosis of activated LN CD4+ T cells in vitro. LN cells from asymptomatic FIV-infected cats will be evaluated for the presence of apoptotic cells by flow cytometry using annexin kit and by immunohistochemistry using TUNNEL assay. The phenotype of the apoptotic cells will be determined by using mAb to feline CD4, CD8, and B21 with appropriate flourochrome labeled system for FACS or counter stain system for immunohistochemistry. In specific aim 3, FIV+ LN CD8+B7+ cells will be cloned in vitro to test whether clonally expanded cells can retain the specific phenotype and function. In specific aim 4, the applicant will test their central hypothesis, that the interaction between the B7 on the activated CD8+T cells and CTLA4 on the activated CD4+ T cells induces the anti-FIV suppressor activity and the CD4+ cell anergy. CTLA4-Ig fusion protein will be used to block the B7 molecules on the CD8+B7+ cells and the effect on the CD4+ cell anergy and FIV suppressor activity will be monitored. Furthermore, both IL2 gene and FIV gag mRNA expression in CD4+ responder cells will also be examined in the CTLA4-Ig blocking studies. The latter studies will determine whether B7-CTLA4 signaling mediates its activity by affecting gene transcription.
此申请是竞争性续订的重新提交 导致 FIV 免疫发病机制丧失的应用 Thl 免疫功能是 HIV 和 FIV 艾滋病的标志。 CD8+, L-选择素-neg、整合素-hi 效应/记忆细胞迅速取代初始 CD8+ 感染 FIV 的猫血液中的细胞,例如 90% 的 CD8+ 细胞 到无症状晚期,血液中的病毒可能具有效应/记忆表型。这 观察结果与艾滋病毒感染者血液中的变化非常相似。 此外,在 FIV 和 HIV 感染中,CD4+、 L-选择素阴性细胞在感染后期出现在循环中 淋巴结中高比例的 T 细胞表达效应/记忆 表型。最近,CD4 T 细胞损失与细胞凋亡增加相关 HIV 感染者的 LN 和免疫激活状态增加, 在非人类灵长类艾滋病模型中。 CD4+ 和 CD8+ T 细胞均增加 B7 分子在 FIV 感染猫的淋巴结中的表达 在整个疾病过程中,细胞类型逐渐增加,例如 它们代表 75-100% 的 LN T 细胞。然而,上调 血液中表达 B7 的 T 细胞数量极少。在许多细胞和动物中 在免疫调节模型中,B7-1 (CD80) 与 CD28 相互作用导致 共刺激激活信号,而 B7-2 (CD86) 与 CTLA4 的相互作用导致 导致此类激活信号的下调或无反应。基于以上 根据观察结果,申请人提出 AIDS 中 CD4+ T 细胞的损失是 由 B7-CTLA4 之间的相互作用产生的无反应性和细胞凋亡引起 CD8+B7+T细胞和活化的CD4+、CTLA4+T细胞。具体目标研究1 将检验他们的假设,即激活淋巴结中的 CD8+B7+ 细胞 FIV感染的猫具有以下表型和功能特征 FIV 抑制细胞。将分析激活的 CD8+B7+ 细胞的 T 细胞 通过 FACS 检测激活标记,通过 RT-qcPCR、FIV 检测细胞因子和趋化因子谱 抑制活性和 CTL 活性。在具体目标 2 中,申请人将 检验他们的假设,即细胞中存在高水平的淋巴细胞凋亡。 无症状 FIV 感染猫的淋巴结,LN CD8+B7+ 细胞 体外诱导活化的 LN CD4+ T 细胞无反应性和凋亡。淋巴结细胞 将评估无症状的 FIV 感染猫是否存在 使用膜联蛋白试剂盒通过流式细胞术和免疫组织化学检测凋亡细胞 使用隧道检测。凋亡细胞的表型将通过以下方式确定 使用带有适当荧光染料标记的猫 CD4、CD8 和 B21 mAb 用于 FACS 的系统或用于免疫组织化学的复染系统。具体来说 目的3、体外克隆FIV+ LN CD8+B7+细胞,测试是否克隆 扩增的细胞可以保留特定的表型和功能。在特定目标下 4、申请人将检验他们的中心假设,即相互作用 激活的 CD8+T 细胞上的 B7 和激活的 CD4+T 细胞上的 CTLA4 之间 细胞诱导抗 FIV 抑制活性和 CD4+ 细胞无反应性。 CTLA4-Ig融合蛋白将用于阻断CD8+B7+上的B7分子 细胞以及对 CD4+ 细胞无反应性和 FIV 抑制活性的影响 被监控。此外,CD4+ 中 IL2 基因和 FIV gag mRNA 表达 应答细胞也将在 CTLA4-Ig 阻断研究中进行检查。这 后续研究将确定 B7-CTLA4 信号传导是否介导其活性 通过影响基因转录。

项目成果

期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
In vivo depletion of CD4+CD25+ regulatory T cells in cats.
猫体内 CD4 CD25 调节性 T 细胞的耗竭。
  • DOI:
    10.1016/j.jim.2007.09.015
  • 发表时间:
    2008
  • 期刊:
  • 影响因子:
    2.2
  • 作者:
    Smithberg,SRochelle;Fogle,JonathanE;Mexas,AngelaM;Reckling,StacieK;Lankford,SusanM;Tompkins,MaryB;Dean,GreggA
  • 通讯作者:
    Dean,GreggA
The role of CD4+CD25+ regulatory T cells in viral infections.
  • DOI:
    10.1016/j.vetimm.2005.07.011
  • 发表时间:
    2005-10
  • 期刊:
  • 影响因子:
    1.8
  • 作者:
    T. Vahlenkamp;M. Tompkins;W. Tompkins
  • 通讯作者:
    T. Vahlenkamp;M. Tompkins;W. Tompkins
Spontaneous T cell apoptosis in feline immunodeficiency virus (FIV)-infected cats is inhibited by IL2 and anti-B7.1 antibodies.
IL2 和抗 B7.1 抗体可抑制感染猫免疫缺陷病毒 (FIV) 的猫的自发 T 细胞凋亡。
  • DOI:
    10.1016/j.vetimm.2004.01.010
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    1.8
  • 作者:
    Bull,MartaE;Vahlenkamp,ThomasW;Dow,JanetL;Collisson,EllenW;Winslow,BarbaraJ;Phadke,AnaghaP;Tompkins,MaryB;Tompkins,WayneAF
  • 通讯作者:
    Tompkins,WayneAF
CD4+CD25+ T regulatory cells activated during feline immunodeficiency virus infection convert T helper cells into functional suppressors through a membrane-bound TGFβ / GARP-mediated mechanism.
  • DOI:
    10.1186/1743-422x-11-7
  • 发表时间:
    2014-01-18
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Miller MM;Petty CS;Tompkins MB;Fogle JE
  • 通讯作者:
    Fogle JE
Lentivirus-induced immune dysregulation.
慢病毒引起的免疫失调。
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Mary B Tompkins其他文献

Mary B Tompkins的其他文献

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{{ truncateString('Mary B Tompkins', 18)}}的其他基金

AIDS Lentivirus-induced TGF-beta+ Treg cells Mediate T cell Immune Dysfunction
艾滋病慢病毒诱导的TGF-β Treg细胞介导T细胞免疫功能障碍
  • 批准号:
    8197195
  • 财政年份:
    2008
  • 资助金额:
    $ 27.28万
  • 项目类别:
AIDS Lentivirus-induced TGF-beta+ Treg cells Mediate T cell Immune Dysfunction
艾滋病慢病毒诱导的TGF-β Treg细胞介导T细胞免疫功能障碍
  • 批准号:
    7994838
  • 财政年份:
    2008
  • 资助金额:
    $ 27.28万
  • 项目类别:
AIDS Lentivirus-induced TGF-beta+ Treg cells Mediate T cell Immune Dysfunction
艾滋病慢病毒诱导的TGF-β Treg细胞介导T细胞免疫功能障碍
  • 批准号:
    7619371
  • 财政年份:
    2008
  • 资助金额:
    $ 27.28万
  • 项目类别:
AIDS Lentivirus-induced TGF-beta+ Treg cells Mediate T cell Immune Dysfunction
艾滋病慢病毒诱导的TGF-β Treg细胞介导T细胞免疫功能障碍
  • 批准号:
    7739491
  • 财政年份:
    2008
  • 资助金额:
    $ 27.28万
  • 项目类别:
Cytomation MoFlo cytometer and high-speed cell sorter
Cytomation MoFlo 细胞仪和高速细胞分选仪
  • 批准号:
    6581548
  • 财政年份:
    2003
  • 资助金额:
    $ 27.28万
  • 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV-INFECTED CATS
感染 5 种猫的 TH1 免疫功能丧失
  • 批准号:
    6646453
  • 财政年份:
    1995
  • 资助金额:
    $ 27.28万
  • 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV INFECTED CATS
五只受感染的猫失去 TH1 免疫功能
  • 批准号:
    2075116
  • 财政年份:
    1995
  • 资助金额:
    $ 27.28万
  • 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV-INFECTED CATS
感染 5 种猫的 TH1 免疫功能丧失
  • 批准号:
    6213558
  • 财政年份:
    1995
  • 资助金额:
    $ 27.28万
  • 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV INFECTED CATS
五只受感染的猫失去 TH1 免疫功能
  • 批准号:
    2672521
  • 财政年份:
    1995
  • 资助金额:
    $ 27.28万
  • 项目类别:
LOSS OF TH1 IMMUNE FUNCTION IN FIV-INFECTED CATS
感染 5 种猫的 TH1 免疫功能丧失
  • 批准号:
    6373478
  • 财政年份:
    1995
  • 资助金额:
    $ 27.28万
  • 项目类别:
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