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: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165801
• 关键词: Allogenic; Antigens; Blood Cells; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Maintenance; Cell physiology; Cells; Cessation of life; Chronic; Clinic; Clone Cells; Collaborations; Data; Defect; Disease model; Drug or chemical Tissue Distribution; Equilibrium; Erythrocytes; Gene Expression; Generations; Goals; Hand; Hematologic Neoplasms; Hematological Disease; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heterogeneity; Immune; Immunity; Immunophenotyping; Impairment; Inherited; Intestines; Knowledge; Lead; Location; Lung; Lymphoid Tissue; Maintenance; Mediating; Memory; Methods; Minor; Modeling; Mus; Organ; Output; Pathway interactions; Patients; Peripheral; Persons; Phenotype; Procedures; Process; Proliferating; Reporting; Research; Sickle Cell Anemia; Skin; Stem cell transplant; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Tars; Testing; Time; Tissue Grafts; Tissue Model; Tissues; Transgenic Model; Transgenic Organisms; anergy; bacterial H antigen; cell type; congenic; curative treatments; exhaustion; graft vs host disease; graft vs leukemia effect; immune reconstitution; mathematical methods; mathematical model; mouse model; novel; pathogen; recruit; response; self-renewal; vaginal mucosa

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.

异基因造血干细胞移植（alloSCT）可以成为血液病的一种治疗方法 恶性肿瘤以及遗传性和获得性血细胞疾病。同种异体反应性移植物 T 细胞介导移植物抗 白血病（GVL）效应并有助于免疫重建。然而，它们也会攻击正常的宿主组织 引起移植物抗宿主病（GVHD）。 alloSCT 研究的一个中心目标是发现以下方法： 最大限度地减少和治疗已发生的 GVHD，同时相对保留 GVL 和抗病原体免疫力。这有 这是一个挑战，因为大多数 GVHD 疗法都会删除或靶向基本 T 细胞功能，尽管也有一些 有前景的相对 GVHD 特异性的新方法。然而，新的、更具体的方法需要 更好地了解 GVHD。我们考虑了如何在持续且持续的情况下维持 GVHD 的问题。 无限抗原；而在其他模型中，长期暴露于 T 细胞抗原会导致精疲力竭、无能和 删除。一种可能性是 GVHD 是通过同种异体反应效应子的持续产生来维持的 源自次级淋巴组织 (SLT)，转运至 GVHD 靶组织。另一种可能性 也就是说，一旦组织中接种了同种异体反应效应子，GVHD 就会在局部维持，无需大量输入 来自 SLT 衍生的 T 细胞。 GVHD 是否在本地和/或 SLT 中维持，另一个关键问题是是否 尽管抗原持续暴露，但仍有特定的 T 细胞亚群补充效应子；如果被识别， 这些细胞将是理想的目标。我们通过抗病原体免疫来寻找这些问题的指导。 强大的抗病原体 T 细胞反应发生在外周组织中，包括皮肤、肺、肠和阴道 粘膜，所有 GVHD 目标。这种反应可以导致组织内产生新描述的 记忆 T 细胞 (TM) 子集称为组织驻留记忆细胞 (TRM)，它们不循环到其他位置。 当组织中的抗原再次攻击时，TRM 迅速激活、增殖并分化为效应细胞。到 通过实验检验 GVHD 是“局部的”这一假设，我们追踪了单个 GVHD 的克隆后代- 诱导 TCR 转基因 (Tg) CD4+ T 细胞 (TS1) 并发现它们在 GVHD 中分布不均 靶组织，并且与 SLT 中的 TS1 不平衡。这些克隆能够发育出后代 不同的表型，表明启动后存在多种分化途径。重要的是，我们 在具有免疫表型和基因的 GVHD 靶组织中发现 TS1 和同种异体反应性多克隆 T 细胞 表达谱与 TRM 样细胞的表达谱相同。该提案将测试 基本假设是 GVHD 是局部持续的并且维持在 GVHD 目标范围内 组织由 TRM 样细胞提供能量。我们将在 CD4 和 CD8 细胞介导 GVHD 的模型中这样做。我们 将应用严格的统计和数学方法来测试这个想法。如果目标确认了我们的 假设，长期目标是首先开发出专门删除或损害这些 TRM 样细胞的方法 在小鼠模型中，然后在诊所中。