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

摘要：总体目标是鉴定和富集供体树突状细胞（DC）群体， 移植物抗宿主病（GvHD）和改善异基因骨髓移植（allo-BMT）后的存活率。 我们的建议是基于已发表的研究结果，即骨髓移植物和移植物中供体DC的含量 移植受者的血液对临床结果有显著影响，通过减少 GvHD死亡率无复发增加。来自鼠BMT模型系统的临床前数据也显示， 来自骨髓而非G-CSF动员的供体浆细胞样树突状细胞（pDC）通过以下方式提高移植物的存活率： 降低GvHD的严重程度。供体pDC限制GvHD的能力取决于它们的表达， 趋化因子受体，细胞因子，神经肽和分解代谢酶，但不知道是否相同 DC亚群产生所有这些因素，或者是否存在DC的多个亚群，每个亚群具有不同的 功能协调发展的另一个关键问题是供体DC归巢淋巴和GvHD靶器官如何调节T淋巴细胞的增殖。 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- 收集含有免疫调节性DC的移植物的有效方法将有助于这些移植物的应用。 对临床实践的令人兴奋的观察。为了实现我们的总体目标，我们提出了三个具体目标： 目标1.为了鉴定最有效的免疫调节剂的表型和基因表达谱， 存在于骨髓和其它移植物来源中供体DC的亚群。假设：骨髓含有 分泌免疫调节性白细胞介素和趋化因子的DC祖细胞的亚群， 促进供体来源的诱导性Treg（iTreg）的产生。 目标2.明确供体骨髓DC祖细胞限制GvHD的机制， 影响供体T细胞的GvL活性。假设：骨髓含有DC祖细胞的亚群 其通过在GVHD靶组织中从幼稚供体T细胞产生iT-reg来限制GvHD，而GvL是介导的， 由供体T细胞在次级淋巴器官中激活。 目标3。确定一种能产生一定数量干细胞的干细胞动员方法， 免疫调节DC祖细胞数量增加假设：用短- Flt 3-L的疗程将增加免疫调节供体DC的数量， 将这些DC和造血干细胞动员到血液中，在那里它们可以通过单采血液成分术收集。 我们的工作，以确定机制，DC调节免疫异基因骨髓移植将通知广泛的医学领域。

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.