Th1/Th17 Macrophage Interactions in Cutaneous GVHD

描述(申请人提供)：异基因干细胞移植(Allo-SCT)仍然是高危急性白血病、低级别淋巴恶性肿瘤、骨髓增生异常综合征患者最活跃的治疗方法，并越来越多地用于复发淋巴恶性肿瘤患者。然而，在那些可以从allo-SCT中受益的患者中，只有25%-30%的患者接受了这种治疗，因为在接受移植的患者中，移植物抗宿主病(GvHD)的风险超过了两个抗原的MHC屏障。急性移植物抗宿主病患者最常见的受累部位是皮肤。同样，慢性移植物抗宿主病患者最常见的受累部位是皮肤纤维化、硬皮病，与显著的长期发病率相关。虽然供者T细胞在GvHD的发生中是至关重要的，但这些细胞在急性和慢性GvHD的效应过程中所起的确切作用尚不清楚。以前的工作表明GvHD是由Th1/Tc1 T细胞介导的，尽管使用无法产生或对干扰素？已经出版了。在过去的十年里，已经描述了多个新的T细胞亚群。此外，先前认为T细胞谱系是固定的这一概念已经受到来自我们小组和其他人的数据的挑战，这些数据表明关键转录因子(TF)的表观遗传学改变可以调节T细胞谱系。具体地说，我们的团队和其他人发现，在IL-12存在的情况下，Th17细胞会变成Th1细胞。这些发现为重新研究特定T细胞亚群在急、慢性移植物抗宿主病病理生理学中的作用提供了新的机会。在这个方案中，我们将评估宿主淋巴组织中供体T细胞的初始极化是由IL-6、IL-1？接受条件反射治疗后的血清肿瘤坏死因子水平。随后，宿主细胞分泌IL-12导致向Th1极化的切换，并将这些细胞迁移到GvHD靶器官。此外，我们还将评估在急性和慢性GvHD期间导致皮肤炎症的T细胞的表型。我们假设急性GvHD是由招募M1巨噬细胞的Th1/Th17细胞介导的，而慢性GvHD是由招募M2巨噬细胞和成纤维细胞的Th17/Th22细胞介导的。我们将重点研究这些细胞在皮肤上募集的重要因素。此外，我们将确定阻断T细胞亚群或特定的巨噬细胞群的功能或迁移是否为皮肤急、慢性移植物抗宿主病的治疗提供了新的途径。 公共卫生相关性：干细胞或骨髓从一个个体移植到另一个个体是治疗急性白血病、骨髓衰竭问题和淋巴系恶性肿瘤的标准方法。然而，这一过程受到供体细胞对宿主的免疫反应性的限制，这种疾病被称为移植物抗宿主病(GvHD)。特定的T细胞群在急性和慢性移植物抗宿主病(GvHD)的发生中所起的作用尚不清楚。这项建议的重点是了解T细胞亚群在急性和慢性GvHD发生中所起的作用，并特别关注皮肤GvHD的病理生理学。

DESCRIPTION (provided by applicant): Allogeneic stem cell transplantation (Allo-SCT) remains the most active therapy for patients with high risk acute leukemia, low grade lymphoid malignancies, myelodysplastic syndromes and is increasingly used in patients with relapsed lymphoid malignancies. However, only 25-30% of patients who could benefit from allo-SCT receive this therapy due to the risk of graft-versus-host disease (GvHD) in patients undergoing transplantation across greater than a two antigen MHC barrier. The most common site of involvement for patients with acute GvHD is the skin. Similarly, the most common site of involvement in patients with chronic GvHD is the skin with fibrotic, sclerodermatous changes associated with significant long term morbidity. While donor T cells are critically required for th occurrence of GvHD, the exact role played by these cells in the effector processes during acute and chronic GvHD is not clear. Previous work had suggested that GvHD was mediated by Th1/Tc1 T cells, although conflicting data using mice unable to generate or respond to IFN-? has been published. Over the past decade, multiple new subsets of T cells have been described. Additionally, the previous notion that T cell lineages are fixed has been challenged by data from our group and others suggesting that epigenetic alterations of critical transcription factors (TFs) can modulate T cell lineages. Specifically, our group and others have found that Th17 cells in the presence of IL-12 become Th1 cells. These findings provide a new opportunity to reexamine the role of specific T cell subsets in the pathophysiology of acute and chronic GvHD. In this proposal, we will evaluate the hypothesis that the initial polarization of donor T cells in host lymphoid tissue is toward the Th17 lineage mediated by the elaboration of IL-6, IL-1? and TNF after receipt of conditioning therapy. Subsequently, the elaboration of IL-12 by host cells leads to a switch to Th1 polarization and the migration of these cells to GvHD target organs. Additionally, we will evaluate the phenotype of T cell responsible for inflammation in the skin during acute and chronic GvHD. We hypothesize that acute GvHD involving the skin is mediated by Th1/Th17 cells that recruit M1 macrophages while chronic GvHD is mediated by Th17/Th22 cells that recruit M2 macrophages and fibroblasts. We will focus on factors important for the recruitment of these cells to the skin. Furthermore, we will determine if blocking the function or migration of T cell subsets or particular populations of macrophages provides a new approach for the therapy of cutaneous acute and chronic GvHD. PUBLIC HEALTH RELEVANCE: The transplantation of stem cells or bone marrow from one individual to another is a standard approach for the treatment of acute leukemia, bone marrow failure problems and lymphoid malignancies. However, this process is limited by the immune reactivity of donor cells against the host termed graft-versus-host disease (GvHD). The role that particular groups of T cells play in the occurrence of acute and chronic graft-versus-host disease (GvHD) is not clear. The focus of this proposal is to understand the role that T cell subsets play in the occurrence of acute and chronic GvHD with a particular focus on the pathophysiology of GvHD in the skin.