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.

同种异体造血干细胞移植（同种）可以是血液学的治疗疗法 损害以及遗传和获得的血细胞疾病。同种异体移植物T细胞介导移植物-VS- 白血病（GVL）作用并有助于免疫重建。但是，它们也攻击正常的宿主组织 引起移植-VS宿主病（GVHD）。 Allosct研究的一个核心目标是发现 通过GVL和抗病原体免疫相对保留，最大程度地减少和处理已建立的GVHD。这就是 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，尽管有一些 有希望的新的相对GVHD特定的方法。但是，新的和更具体的方法需要一个 更好地了解GVHD。我们考虑了如何保持GVHD持久性和 无限抗原；而在其他模型中，慢性T细胞抗原的暴露会导致疲惫，反应和 删除。一种可能性是GVHD通过连续产生同种异体作用来维持 源自二级淋巴组织（SLT），该组织流动到GVHD靶组织。另一种可能性 IS，一旦将组织带有同种反应性效应，GVHD将在本地维持，而没有明显的输入 来自SLT衍生的T细胞。 GVHD是否在本地和/或SLT中维护，另一个关键问题是是否是 尽管持续的抗原暴露，但仍有特定的T细胞子集复制效应子；如果确定， 这样的细胞将是靶向的理想选择。我们正在寻求抗疾病免疫，以寻求这些问题的指导。 强大的抗疾病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。这种反应会导致新描述的组织内的产生 记忆T细胞（TM）子集称为组织居民记忆细胞（TRM），该记忆细胞（TRM）不会循环到其他位置。 在组织中的抗原补偿时，TRM迅速激活，增殖并分化为效果。到 通过实验检验了GVHD是“局部”的假设，我们跟踪了单个GVHD-的克隆进度 诱导TCR转基因（TG）CD4+ T细胞（TS1），发现它们不均分布在GVHD中 目标时机，而不是在SLT中与TS1保持平衡。这些克隆能够与 各种表型，表明启动后可用多个分化途径。重要的是，我们 在GVHD靶时间内发现了具有免疫表型和基因的GVHD靶向时间内的TS1和同种反应性多克隆T细胞 与报告的TRM样细胞报告的表达谱。该建议将测试 基本假设是GVHD在本地维持，并且在GVHD目标中维护 组织被TRM样细胞燃烧。我们将在CD4和CD8细胞介导GVHD的模型中这样做。我们 将采用严格的统计和数学方法来测试这一想法。如果目的确认我们的 假设，长期目标是开发特异性删除或损害这些TRM样细胞的方法，首先 在小鼠模型中，然后在诊所中。