Th1/Th17 Macrophage Interactions in Cutaneous GVHD

描述（由申请人提供）：同种异体干细胞移植（Allo-SCT）仍然是高危急性白血病、低度淋巴恶性肿瘤、骨髓增生异常综合征患者最活跃的治疗方法，并且越来越多地用于复发性淋巴恶性肿瘤患者。然而，只有25-30%可以从allo-SCT中受益的患者接受这种治疗，因为在接受超过两个抗原MHC屏障的移植的患者中存在移植物抗宿主病（GvHD）的风险。急性GvHD患者最常见的受累部位是皮肤。类似地，患有慢性GvHD的患者中最常见的受累部位是具有与显著的长期发病率相关的纤维化、硬皮病性变化的皮肤。虽然供体T细胞是GvHD发生的关键，但这些细胞在急性和慢性GvHD期间的效应过程中发挥的确切作用尚不清楚。先前的工作表明GvHD是由Th 1/Tc 1 T细胞介导的，尽管已经发表了使用不能产生或响应IFN-γ的小鼠的相互矛盾的数据。在过去的十年中，已经描述了多个新的T细胞亚群。此外，以前认为T细胞谱系是固定的观点受到了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）的表观遗传改变可以调节T细胞谱系。具体地说，我们的小组和其他人已经发现，在IL-12存在的情况下，Th 17细胞变成Th 1细胞。这些发现提供了一个新的机会，重新审视特定的T细胞亚群在急性和慢性GvHD的病理生理学的作用。在这个建议中，我们将评估的假设，即在宿主淋巴组织中的供体T细胞的初始极化是向Th 17谱系介导的IL-6，IL-1 β和TNF的加工后接受预处理治疗。随后，宿主细胞对IL-12的加工导致向Th 1极化的转变以及这些细胞向GvHD靶器官的迁移。此外，我们将评估在急性和慢性GvHD期间负责皮肤炎症的T细胞表型。我们假设涉及皮肤的急性GvHD由Th 1/Th 17细胞介导，其招募M1巨噬细胞，而慢性GvHD由Th 17/Th 22细胞介导，其招募M2巨噬细胞和成纤维细胞。我们将重点关注这些细胞向皮肤募集的重要因素。此外，我们将确定阻断T细胞亚群或特定巨噬细胞群体的功能或迁移是否为皮肤急性和慢性GvHD的治疗提供了新的方法。

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-γ 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-1ß 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.