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Graft-versus-Host Disease: Local Maintenance in Target Tissues by Tissue Resident Memory-Type Cells.

Graft-versus-Host Disease: Local Maintenance in Target Tissues by Tissue Resident Memory-Type Cells.
移植物抗宿主病:组织驻留记忆型细胞对目标组织的局部维持。
批准号:
10165801
负责人:
Warren D Shlomchik
金额:
$63.26万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-08-15 至 2023-05-31

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中文摘要
翻译
异基因造血干细胞移植(AllSCT)可作为血液病的根治疗法 血液细胞的恶性肿瘤和遗传性及获得性疾病。同种异体反应性移植物T细胞介导移植物抗... 白血病(GVL)起作用并有助于免疫重建。然而,它们也会攻击正常的宿主组织 导致移植物抗宿主病(GVHD)。异基因干细胞移植研究的一个中心目标是发现 尽量减少和治疗已确诊的移植物抗宿主病,相对保留移植物抗宿主病和抗病原体免疫。这有 这是一个挑战,因为大多数GVHD疗法删除或针对基本T细胞功能,尽管有少数 前景看好的相对针对GVHD的新方法。然而,新的和更具体的方法需要 更好地了解GVHD。我们考虑了GVHD如何维持的问题,尽管持续和 而在其他模型中,慢性暴露T细胞抗原会导致精疲力竭、无能和 删除。一种可能性是移植物抗宿主病是由不断产生的同种异体反应效应器维持的 来源于次级淋巴组织(SLT),运输到GVHD靶组织。另一种可能性 就是,一旦组织被植入同种异体反应效应器,GVHD就会在没有大量输入的情况下在局部维持 来自SLT来源的T细胞。GVHD是否在当地和/或在SLT中维持,另一个关键问题是 有特定的T细胞亚群可以补充效应器,尽管不断暴露于抗原;如果被发现, 这样的细胞将是理想的靶子。在这些问题上,我们希望通过抗病原体免疫来获得指导。 强大的抗病原体T细胞反应发生在周围组织中,包括皮肤、肺、肠道和阴道 粘膜,所有GVHD靶点。这种反应可以导致在组织内产生新描述的 称为组织驻留存储单元(TRM)的存储T细胞(TM)子集,其不循环到其他位置。 当抗原在组织中重新攻击时,TRM被迅速激活、增殖并分化为效应器。至 实验验证GVHD是局部的假设,我们跟踪了单个GVHD的克隆后代- 诱导TCR转基因(TG)CD4+T细胞(TS1),发现它们在GVHD中分布不均 靶组织与SLT中的TS1不平衡。这些无性系能够通过 表型多样,提示启动后有多种分化途径可用。重要的是,我们 GVHD靶组织中发现具有免疫表型和基因的TS1和同种异体反应性多克隆T细胞 表达谱与已报道的TRM样细胞的表达谱相似。这项提案将考验 GVHD在当地持续的基本假设以及在GVHD目标内的维持 组织由TRM样细胞提供能量。我们将在CD4和CD8细胞介导GVHD的模型中做到这一点。我们 将应用严格的统计和数学方法来测试这一想法。如果目标确认了我们的 假设,长期目标是开发专门删除或损害这些TRM样细胞的方法,首先 在小鼠模型上,然后在诊所里。
英文摘要
Allogeneic hematopoietic stem cell transplantation (alloSCT) can be a curative therapy for hematologic malignancies and inherited and acquired disorders of blood cells. Alloreactive graft T cells mediate the graft-vs- leukemia (GVL) effect and contribute to immune reconstitution. However, they also attack normal host tissues causing graft-vs-host disease (GVHD). A central goal of alloSCT research has been to discover methods of minimizing and treating established GVHD with relative sparing of GVL and anti-pathogen immunity. This has been a challenge as most GVHD therapies delete or target basic T cell functions, though there are a few promising new relatively GVHD-specific approaches. New and more specific approaches, however, require a better understanding of GVHD. We considered the question of how GVHD is maintained despite persistent and unlimited antigen; whereas in other models, chronic T cell-antigen exposure results in exhaustion, anergy and deletion. One possibility is that GVHD is sustained by the continuous generation of alloreactive effectors derived from secondary lymphoid tissues (SLT), which traffic to GVHD target tissues. An alternative possibility is, that once tissues are seeded with alloreactive effectors, GVHD is maintained locally without significant input from SLT-derived T cells. Whether GVHD is maintained locally and/or in SLT, another key question is whether there are specific subsets of T cells that replenish effectors despite constant antigen exposure; if identified, such cells would be ideal to target. We looked to antipathogen immunity for guidance on these questions. Robust antipathogen T cell responses occur in peripheral tissues, including skin, lung, bowel and vaginal mucosa, all GVHD targets. Such responses can lead to the generation within tissues of a newly described memory T cell (TM) subset called tissue resident memory cells (TRM) which do not circulate to other locations. Upon antigen rechallenge in tissues, TRM are rapidly activated, proliferate and differentiate into effectors. To experimentally test the hypothesis that GVHD is “local”, we tracked the clonal progeny of single GVHD- inducing TCR transgenic (Tg) CD4+ T cells (TS1) and found them to be unequally distributed among GVHD target tissues and not in equilibrium with TS1 in SLT. These clones were capable of developing progeny with diverse phenotypes, suggesting multiple differentiation pathways being available after priming. Importantly, we found TS1 and alloreactive polyclonal T cells within GVHD target tissues with immunophenotypes and gene expression profiles in common with those reported for TRM-like cells. This proposal will test the fundamental hypotheses that GVHD is locally sustained and that maintenance within GVHD target tissues is fueled by TRM-like cells. We will do so in models wherein CD4 and CD8 cells mediate GVHD. We will apply rigorous statistical and mathematical approaches to test this idea. If the Aims confirm our hypotheses, the long-term goal is to develop methods to specifically delete or impair these TRM-like cells, first in mouse models, and then in the clinic.
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Mechanisms whereby IFN-gamma sensitizes AML to the graft-vs-leukemia effect
Mechanisms whereby IFN-gamma sensitizes AML to the graft-vs-leukemia effect
Mechanisms whereby IFN-gamma sensitizes AML to the graft-vs-leukemia effect
Graft-versus-Host Disease: Local Maintenance in Target Tissues by Tissue Resident Memory-Type Cells.
国内基金
海外基金
Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
  • 批准号:
    2022J011295
  • 项目类别:
    省市级项目
  • 资助金额:
    10.0万元
  • 批准年份:
    2022
  • 负责人:
    王亚伟
  • 依托单位:
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究