REGULATION OF IMMUNE RESPONSES IN HUMANS AND NON-HUMAN PRIMATES

人类和非人类灵长类动物免疫反应的调节

• 批准号: 2566773
• 负责人: W STROBER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2566773
• 关键词: B lymphocyte; CD2 molecule; CD3 molecule; T cell receptor; T lymphocyte; animal tissue; apoptosis; autoimmunity; biological signal transduction; cell cell interaction; clinical research; cytokine; cytotoxic T lymphocyte; helper T lymphocyte; human tissue; immunoregulation; interferon gamma; interleukin 2; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; tissue /cell culture

Project 1: Autoimmune Lymphoproliferative Syndrome is a disorder characterized by massive expansion of a CD4-/CD8- T cell population and autoimmunity similar to that in lpr mice. Recently, it has been shown that both ALPS patients and lpr mice have mutations of the FAS gene and Defective apoptosis. Here, we report on immune function in ALPS patients. In initial studies we showed that the circulating level of IL-10 was greatly elevated I all ALPS patients in rough proportion to their level of CD4-/CD8- T cells. In addition, while plasma levels of TNFalpha were increased 3 - 9 fold, levels of IL-1 and IL-6 were normal. I subsequent studies, we determined cytokine production (IL-4, IL-5 IFN-gamma, Il-2) in cultured ALPS T cell subpopulations stimulated with alphaCD3/alphaCD28 or alphaCD2/alphaCD28. We showed that ALPS patients CD4+/DR+ T cells produced increased amounts of IL-4 and IL-5 (10-30 fold, n=6) and decreased amounts of IFN-gamma (2-4 fold, n=6) as compared to CD4+/DR+ T cells of controls (n=4). In parallel studies, we showed that ALPS patient peripheral B (stimulated with SAC and IL-2) and T cells (stimulated as above) produced decreased amounts of IL-10 (3-10 fold) whereas patient peripheral monocytes (stimulated with LPS) produced increased amounts of IL-10 (5 fold, n=3) as compared to control cells. Finally, we determined that patient monocytes (stimulated with LPS/IFN-gamma) produces 30-fold less Il-12 than normal cells. In conclusion, ALPS is associated with the presence of DR+ T cells which respond upon stimulation with a Th2-type cytokine profile; this, plus the increased production of IL-10 defines a cytokine mileau heading to autoimmunity. Project 2: Lamina propria, (LP) T cells are partially anergic T cells that respond poorly to a proliferative stimulus delivered via the TCR/CD3 pathway, but retain considerable ability to respond to a stimulus delivered via the CD2 co-stimulatory or accessory pathway. In the present study, we showed first that unstimulated LP T cells, as compared to unstimulated peripheral blood (PB) T cells, exhibit an increased level of apoptosis which is further increased following CD2 pathway stimulation, but not following via TCR/CD3 pathway stimulation. These results are in contrast to those obtained with PB T cells where neither stimulation via TCR/CD3 nor CD2 pathways increased the level of apoptosis above low baseline levels. We next showed that IL-2 had a sparing effect of apoptosis of unstimulated LP T cells in that IL-2 decreased and anti-IL-2 increased apoptosis of these cells; in contrast, IL-2 had no effect of apoptosis of CD2-pathway-stimulated cells. Finally, we showed that the increased apoptosis of LP T cells induces by CD2-pathway stimulation is inhibited when the Fas Antigen is blocked by a non-stimulatory anti-Fas antibody. Thus, these studies suggest that LP T cells are characterized by an increased susceptibility to Fas-mediated apoptosis most due to a "downstream" change in the Fas signaling pathway.

项目1：自身免疫性肿瘤增生综合征是一种疾病 其特征在于CD 4-/CD 8- T细胞群的大量扩增， 与LPR小鼠相似的自身免疫性。 最近，有证据表明， ALPS患者和lpr小鼠都有FAS基因突变， 凋亡缺陷。 在这里，我们报告的免疫功能在ALPS 患者 在最初的研究中，我们发现， 在所有ALPS患者中，IL-10显著升高， CD 4-/CD 8- T细胞水平。 此外，虽然血浆中的 TNF α升高3 - 9倍，IL-1和IL-6水平正常。 在随后的研究中，我们测定了细胞因子（IL-4，IL-5 IFN-γ，IL-2）在用 α CD 3/α CD 28或α CD 2/α CD 28。 我们发现ALPS患者 CD 4 +/DR+ T细胞产生增加量的IL-4和IL-5（10-30倍， n=6）和IFN-γ的量减少（2-4倍，n=6）， 对照组（n=4）的CD 4 +/DR+ T细胞。 在平行研究中，我们发现， ALPS患者外周B细胞（用SAC和IL-2刺激）和T细胞 （如上刺激）产生减少量的IL-10（3-10倍） 而患者外周血单核细胞（用LPS刺激）产生 与对照细胞相比，IL-10的量增加（5倍，n=3）。 最后，我们确定患者单核细胞（用 LPS/IFN-γ）产生的IL-12比正常细胞少30倍。 在 结论：ALPS与DR+ T细胞的存在有关， Th 2型细胞因子谱刺激后的反应;这一点，加上 IL-10产生的增加定义了一个细胞因子里程碑， 自身免疫项目2：固有层，（LP）T细胞部分 无反应性T细胞对所递送的增殖刺激反应不良， 通过TCR/CD 3途径，但保留相当大的能力， 通过CD 2共刺激或辅助途径传递的刺激。在 在本研究中，我们首先表明，未受刺激的LP T细胞， 与未刺激的外周血（PB）T细胞相比， 增加的细胞凋亡水平，在CD 2 途径刺激，但不遵循通过TCR/CD 3途径刺激。 这些结果与用PB T细胞获得的结果相反， 通过TCR/CD 3或CD 2途径的刺激均不增加 细胞凋亡高于低基线水平。 我们接下来发现IL-2有一个 IL-2对未受刺激LP T细胞凋亡的保护作用 减少和抗IL-2增加这些细胞的凋亡;相反， IL-2对CD 2通路刺激的细胞凋亡无影响。 最后，我们发现，LPT细胞的凋亡增加是由 当Fas抗原被阻断时，CD 2途径刺激被抑制， 非刺激性抗Fas抗体。 因此，这些研究表明， LP T细胞的特征在于对以下疾病的易感性增加： Fas介导的细胞凋亡主要是由于Fas的“下游”变化， 信号通路