Role of monocytes and Th17 cells in the pathogenesis of graft-versus-host disease - influence of S100 proteins and Hsp90

单核细胞和 Th17 细胞在移植物抗宿主病发病机制中的作用 - S100 蛋白和 Hsp90 的影响

• 批准号: 273124679
• 负责人: Professorin Dr. Ursula Holzer
• 金额: --
• 依托单位: Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/273124679?language=en
• 关键词: Role; monocytes; Th17; cells; pathogenesis

Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic stem cell transplantation. However, the pathophysiology of GvHD is not fully understood. Our group could demonstrate that in vivo activated monocytes of patients with acute or chronic GvHD induced higher levels of Th17 cells compared to monocytes of patients without GvHD. In the proposed project monocytes as well as monocyte-induced Th17 cells of patients with acute or chronic GvHD will be characterized. In autoimmune diseases it is known that the CD14+CD16+ proinflammatory monocyte subpopulation can be divided into two subgroups: CD14+CD16++ monocytes and CD14++CD16+ monocytes whereby the latter induces high levels of proinflammatory Th17 cells. In this project the percentage of these monocyte subpopulations will be determined and sorted in patients with and without acute or chronic GvHD. A subgroup of IL-17 producing T cells (Th17.1 cells) express the p-glycoprotein (multi-drug resistance type 1 protein (MDR1)) and are resistant to immunosuppression with glucocorticoids. Therefore, the sorted monocyte subpopulations will be analyzed in terms of induction of MDR-Th17 and MDR+Th17.1 cells. Additionally, the influence of immunoregulation e.g. regulatory T cells (Tregs), TGFbeta or glucocorticoids on monocyte-induced Th17 cells of patients with GvHD will be investigated. Correlating our results with the clinical course of the studied patients we would like to prove the hypothesis that patients with high risk for developing severe or chronic GvHD might be identified by elevated levels of CD14++CD16+ monocytes or Th17.1 cells. This may allow the implementation of risk stratified therapeutic approaches. Furthermore, the impact of S100 proteins as known amplifier of inflammation and their interplay with heat shock protein (Hsp) 90 will be investigated in monocytes. In our previous work, elevated levels of S100 proteins could be detected in the bowel tissue, stool and serum of patients with acute and chronic GvHD demonstrating the release of these phagocyte-specific proteins during GvHD. Stimulation of monocytes with S100 proteins was found to promote Th17 development which could be inhibited by blockade of Hsp90. Therefore, the intersection of the signaling pathways of S100 proteins and Hsp90 will be investigated by microarray analysis and verified on protein level in the planned study. The understanding of the mechanisms of activation and regulation of inflammatory cells in GvHD is essential for the identification of central factors underlying the destroying inflammation of this disease. Our results pave the way for novel specific therapeutic strategies, e.g. inhibition of Hsp90 in these often multimorbid patients.

移植物抗宿主病（GvHD）是异基因干细胞移植后发病和死亡的主要原因。然而，GvHD的病理生理学尚未完全了解。我们的小组可以证明，与没有GvHD的患者的单核细胞相比，患有急性或慢性GvHD的患者的体内活化的单核细胞诱导更高水平的Th 17细胞。在所提出的项目中，将表征患有急性或慢性GvHD的患者的单核细胞以及单核细胞诱导的Th 17细胞。在自身免疫性疾病中，已知CD 14 + CD 16+促炎单核细胞亚群可分为两个亚群：CD 14 + CD 16 ++单核细胞和CD 14 ++ CD 16+单核细胞，其中后者诱导高水平的促炎Th 17细胞。在该项目中，将在患有和不患有急性或慢性GvHD的患者中确定和分选这些单核细胞亚群的百分比。产生IL-17的T细胞（Th17.1细胞）的亚群表达p-糖蛋白（多药耐药1型蛋白（MDR 1））并且对糖皮质激素的免疫抑制具有抗性。因此，将根据MDR-Th 17和MDR+Th17.1细胞的诱导分析分选的单核细胞亚群。此外，将研究免疫调节例如调节性T细胞（TcB）、TGF β或糖皮质激素对患有GvHD的患者的单核细胞诱导的Th 17细胞的影响。将我们的结果与所研究患者的临床过程相关联，我们想要证明具有发展严重或慢性GvHD的高风险的患者可以通过升高的CD 14 ++ CD 16+单核细胞或Th17.1细胞水平来鉴定的假设。这可能允许实施风险分层治疗方法。此外，S100蛋白作为已知的炎症放大器的影响及其与热休克蛋白（Hsp）90的相互作用将在单核细胞中进行研究。在我们以前的工作中，在急性和慢性GvHD患者的肠组织、粪便和血清中可以检测到升高水平的S100蛋白，这表明在GvHD期间这些吞噬细胞特异性蛋白的释放。刺激单核细胞与S100蛋白被发现，以促进Th 17的发展，这可以被抑制Hsp 90的封锁。因此，S100蛋白和Hsp 90信号通路的交叉将通过微阵列分析进行研究，并在计划的研究中在蛋白水平上进行验证。了解GvHD中炎症细胞的激活和调节机制对于识别这种疾病的破坏性炎症的核心因素至关重要。我们的研究结果为新的特异性治疗策略铺平了道路，例如在这些经常患有多种疾病的患者中抑制Hsp 90。

项目成果

Increase of Intermediate Monocytes in Graft-versus-Host Disease: Correlation with MDR1+Th17.1 Levels and the Effect of Prednisolone and 1α,25-Dihydroxyvitamin D3.

移植物抗宿主病中中间单核细胞的增加：与 MDR1 Th17 1 水平的相关性以及泼尼松龙和 1α,25-二羟基维生素 D3 的作用

• DOI: 10.1016/j.bbmt.2017.08.008
• 发表时间: 2017
• 期刊: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
• 作者: Reinhardt-Heller K;Hirschberg I;Lang P;Vogl T;Handgretinger R;Wolfgang A. Bethge W;Holzer U
• 通讯作者: Holzer U