Using donor dendritic cells to optimize GvHD and GvL in allogeneic stem cell transplantation

摘要：首要目标是识别和丰富供者树突状细胞(DC)群体，使其减少 移植物抗宿主病(GvHD)和提高异基因骨髓移植(allo-BMT)后的存活率。 我们的建议是基于已发表的研究结果，即供者DC在骨髓移植中和在 移植受者的血液对临床结果有重大影响，通过减少 GVHD--不增加复发的死亡率。来自小鼠骨髓移植模型系统的临床前数据也表明 来自骨髓的供者浆细胞样树突状细胞(PDC)而不是G-CSF动员的移植物通过以下方式提高存活率 减轻GvHD的严重程度。供体PDC限制GvHD的能力取决于其表达的 趋化因子受体、细胞因子、神经肽和分解代谢酶，但尚不清楚是否相同 DC子集产生所有这些因素，或者是否存在多个DC子群体，每个子群体具有不同的 功能。另一个关键问题是供者DC归巢到淋巴和GvHD靶器官如何调节T细胞 细胞免疫包括GvHD和移植物抗白血病(GVL)。回答这些问题并确定成本- 收集含有免疫调节树突状细胞的移植物的有效程序将促进这些应用 临床实践中令人兴奋的观察。为了朝着我们的总体目标前进，我们提出了三个具体目标： 目的1.鉴定最有效的免疫调节因子的表型和基因表达谱 骨髓和其他移植物来源中存在的供体DC亚群。假设：骨髓含有 DC祖细胞亚群，分泌免疫调节白介素和趋化因子，通过以下方式限制GvHD 促进供体来源的诱导Treg(ITreg)的产生。 目的2.明确供者骨髓DC祖细胞限制GvHD的机制。 影响供者T细胞的GVL活性。假设：骨髓含有DC祖细胞亚群 这通过在GVHD靶组织中由幼稚的供者T细胞产生it-reg来限制GvHD，同时GVL被介导 供者的T细胞在次级淋巴器官中被激活。 目的3.确定一种干细胞动员方法，以产生移植的干细胞数量和 免疫调节性DC祖细胞数量增加假说：对供者进行短期- 免疫调节性供者树突状细胞增多与单次注射普利沙福联合应用的研究 会将这些DC和造血干细胞动员到血液中，在那里可以通过分离收集它们。 我们为确定DC调节allo-BMT免疫的机制所做的工作将为医学的广泛领域提供信息。

ABSTRACT: The overarching goal is to identify and enrich donor dendritic cell (DC) populations that reduce graft-versus-host disease (GvHD) and improve survival after allogeneic bone marrow transplantation (allo-BMT). Our proposal is grounded on published findings that the content of donor DC in the bone marrow graft and in the blood of transplant recipients have significant impact on clinical outcomes, improving survival by decreasing GvHD-mortality without increasing relapse. Preclinical data from murine BMT model systems also show that donor plasmacytoid dendritic cells (pDC) from bone marrow but not G-CSF mobilized grafts improve survival by decreasing the severity of GvHD. The ability of donor pDC to limit GvHD is dependent upon their expression of chemokine receptors, cytokines, neuropeptides and catabolic enzymes, but it is not known whether the same DC subset produces all these factors, or whether there are multiple sub-populations of DC, each with different functions. Another key question is how homing of donor DC to lymphoid and GvHD-target organs regulates T cell immunity including GvHD and graft-versus-leukemia (GvL). Answering these questions and identifying cost- effective procedures for collecting grafts containing immune-regulatory DC will facilitate application of these exciting observations to clinical practice. To progress towards our overall goal, we propose three specific aims: Aim 1. To identify the phenotype and gene expression profile of the most potent immuno-regulatory subset of donor DC present in bone marrow and other graft sources. Hypothesis: bone marrow contains subsets of DC progenitors that secrete immune-regulatory interleukins and chemokines that limit GvHD by facilitating the generation of donor-derived induced-Treg (iTreg). Aim 2. To define the mechanism by which donor bone marrow DC progenitors limit GvHD without affecting the GvL activity of donor T cells. Hypothesis: bone marrow contains a subset of DC progenitors that limit GvHD by generating iT-reg from naïve donor T cells in GVHD target tissues while GvL is mediated by donor T cells activated in secondary lymphoid organs. Aim 3. To define a stem cell mobilization approach that yields an engrafting number of stem cells and increased numbers of immuno-regulatory DC progenitors Hypothesis: treatment of donors with a short- course of Flt3-L will increase the numbers of immune-regulatory donor DC and a single injection of plerixafor will mobilize these DC and hematopoietic stem cells into the blood where they can be collected by apheresis. Our work to define mechanisms by which DC regulate immunity in allo-BMT will inform broad fields of medicine.