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: 9756456
• 负责人: Warren D Shlomchik
• 金额: $ 65.56万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756456
• 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; Expression Profiling; 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）可以是血液病的治愈性疗法。 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）影响并有助于免疫重建。然而，它们也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 最小化和治疗已建立的GVHD，相对保留GVL和抗病原体免疫。这 这是一个挑战，因为大多数GVHD疗法删除或靶向基本的T细胞功能，尽管有一些 有希望的新的相对GVHD特异性的方法。然而，新的、更具体的方法需要 更好地了解GVHD。我们考虑了GVHD是如何维持的问题， 无限制的抗原;而在其他模型中，慢性T细胞抗原暴露导致衰竭，无反应性， 删除。一种可能性是GVHD是通过同种异体反应性效应物的持续产生来维持的 来源于次级淋巴组织（GVHD），其运输至GVHD靶组织。另一种可能性 一旦组织接种同种异体反应性效应物，GVHD在局部维持而没有显著输入 来自SLT衍生的T细胞。无论GVHD是在本地和/或在本地维持，另一个关键问题是， 尽管持续的抗原暴露，仍存在补充效应子的特定T细胞亚群;如果鉴定出， 这样的细胞将是理想的目标。我们从抗病原体免疫学中寻找这些问题的答案。 强大的抗病原体T细胞反应发生在外周组织，包括皮肤，肺，肠和阴道 粘膜，所有GVHD靶标。这种反应可以导致组织内产生一种新描述的 记忆T细胞（TM）子集称为组织驻留记忆细胞（TRM），其不循环到其他位置。 在组织中抗原再激发后，TRM迅速活化、增殖并分化为效应物。到 为了实验性地检验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）CD 4 + T细胞（TS 1），发现它们在GVHD中分布不均匀 靶组织，并且不与TS 1平衡。这些克隆能够发育后代， 不同的表型，表明引发后可获得多种分化途径。重要的是我们 在GVHD靶组织中发现TS 1和同种异体反应性多克隆T细胞，其免疫表型和基因 表达谱与TRM样细胞报道的表达谱相同。这项提案将考验 基本假设GVHD是局部持续的，维持在GVHD目标范围内 组织由TRM样细胞提供能量。我们将在其中CD 4和CD 8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验证这一想法。如果目标确认我们的 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 在小鼠模型中，然后在临床上。