MicroRNA Regulates Graft-versus-Host Disease

 描述（由申请人提供）：造血细胞移植（HCT）可以治愈多种良性和恶性造血系统疾病，但急性和慢性移植物抗宿主病（GVHD）仍然是移植相关发病、残疾和死亡的主要病例，从而限制了HCT的使用。虽然在理解GVHD的病理生理学方面不断取得进展，但在理解GVHD中调节同种异体T和B细胞致病性的分子机制方面存在显著差距。最近的证据表明，microRNAs（miRs），一类小的非编码RNA，在协调免疫反应中发挥重要作用。miR-17-92簇编码6个miR，在抗感染、抗肿瘤和自身免疫等多种免疫应答中发挥重要作用。然而，该簇在GVHD和移植物抗白血病（GVL）中调节T细胞和B细胞应答的作用尚未探讨。我们的长期目标是通过靶向人类miR-17-92簇来预防和治疗GVHD，同时保留HCT后的GVL效应。本提案的目的是在小鼠临床前骨髓移植（BMT）模型中实现这一目标。中心假设是miR-17-92控制T细胞和B细胞活化和同种异体反应中的功能，因此阻断该簇将显著减轻急性和慢性GVHD，同时保留GVL活性。我们的初步研究强烈支持这一假设，其中我们发现miR-17-92缺陷型T细胞在同种异体BMT的鼠模型中引起急性GVHD的能力显著降低，同时保留GVL活性。此外，合成的抗miR-17或抗miR-19锁核酸（LNA）引物也显著降低供体T细胞扩增、IFN γ产生和GVHD严重程度。在当前的提议中，我们将通过追求3个特定目的来验证我们的假设并实现目标：1）确定miR-17-92在aGVHD和GVL效应中的T细胞应答中的作用; 2）确定miR-17-92在cGVHD中的T细胞和B细胞应答中的作用; 3）评估阻断miR-17-92在GVHD和GVL活性中的作用。这些研究有望增强我们对miR-17-92在调节T细胞和B细胞应答中的作用的理解，并验证miR-17-92作为控制GVHD的治疗靶点，同时保留GVL活性。

 DESCRIPTION (provided by applicant): Hematopoietic cell transplantation (HCT) can cure a variety of benign and malignant hematopoietic disorders, but acute and chronic graft-versus-host disease (GVHD) remains the primary case of transplant-related morbidity, disability and mortality, thereby limiting the use of HCT. Although progress in understanding the pathophysiology of GVHD has been continually made, there are significant gaps in understanding molecular mechanisms that regulate the pathogenicity of allogeneic T and B cells in GVHD. Recent evidence demonstrates that microRNAs (miRs), a class of small noncoding RNAs, play a significant role in orchestrating immune responses. miR-17-92 cluster encodes 6 miRs and plays an important role in a variety of immune responses including anti-infection, anti-tumor and autoimmunity. However, the role of this cluster in the modulation of T- and B-cell responses in GVHD and graft-versus-leukemia (GVL) has not been explored. Our long-term goal is to prevent and treat GVHD while preserving the GVL effect after HCT by targeting miR-17-92 cluster in humans. The objective of this proposal is to achieve this goal in pre-clinical bone marrow transplantation (BMT) models in mice. The central hypothesis is that miR-17-92 controls T- and B-cell activation and function in alloresponse, and thus blockade of this cluster will significantly alleviate acute and chronic GVHD while preserving GVL activity. This hypothesis is strongly supported by our preliminary studies, where we found that miR-17-92-deficient T cells had significantly reduced ability to cause acute GVHD while retaining GVL activity in murine models of allogeneic BMT. Furthermore, synthetic anti-miR-17 or anti-miR-19 locked nucleic acid (LNA) antagomirs also significantly reduced donor T-cell expansion, IFN production, and GVHD severity. In current proposal, we will test our hypothesis and accomplish the objectives by pursuing 3 Specific Aims: 1) To define the role of miR-17-92 in T-cell response in aGVHD and GVL effect; 2) To determine the role of miR-17-92 in T-cell and B-cell response in cGVHD; 3) To evaluate the effects of blocking miR-17-92 in GVHD and GVL activity. The proposed studies are expected to enhance our understanding in the roles of miR-17-92 in regulating T- and B-cell responses, and to validate miR-17-92 as therapeutic targets for the control of GVHD while preserving GVL activity.