Tolerogenic DC as Therapeutic Agents in GVHD

项目总监/首席调查员(最后、第一、中间)：屠夫，尤金C.1R01 AI082318-01 我们这项为期两年的奖项的目标是详细定义最近发现的耐受性DC群体在移植物抗宿主病(GVHD)中的治疗潜力。我们最近发现表达CCR9的血浆细胞样树突状细胞是一种极具耐受性的树突状细胞亚群。我们的初步研究表明，存活的同种异体CCR9+PDCs抑制由异基因骨髓和效应者CD4+T细胞重组的受者的GVHD。在这里，在GVHD模型中，耐受性PDC对诱导的同种特异性耐受的有效性和持久性的要求将在以下研究中表征：a)PDC数量在最佳清髓受体条件下的作用，b)固定的或非增殖性的耐受性PDDC抑制GVHD的能力，以及c)CCR9本身在耐受诱导中的作用。为了验证pDC特别适合GVHD治疗的假设，将这些高度耐受的pDC与假定的耐受性髓系树突状细胞群体进行GVHD抑制潜能比较。移植物抗宿主反应针对正常宿主组织是有害的，但在治疗抗肿瘤(移植物抗肿瘤或GVT)方案中可能是有益的。调节性T细胞(Tregs)可以控制全身性GVHD，同时允许GVT活动。为了验证CCR9+pDC可以在不消除GVT的情况下抑制GVHD的假设，我们将在小鼠白血病模型上进行实验。总之，这些研究将详细定义CCR9+pDC在模拟人类患者遇到致病GVHD反应的情景中抑制GVHD有害影响的潜力。

Program Director/Principal Investigator (Last, First, Middle): Butcher, Eugene C. 1R01 AI082318-01 Our goal for this 2 year award is to define in detail the therapeutic potential of recently identified tolerogenic DC populations in graft versus host disease (GVHD). We have recently identified CCR9- expressing plasmacytoid DCs as an extremely potent tolerogenic subset of DCs. Our initial studies indicate that viable allogeneic CCR9+ pDCs inhibit GVHD in irradiated recipients reconstituted with allogeneic bone marrow and effector CD4+ T cells. Here, tolerogenic pDC requirements for effectiveness and durability of induced allo-specific tolerance in the GVHD model will be characterized in studies examining a) the role of pDC numbers in the context of optimal myeloablative recipient conditioning regimens, b) the ability of fixed or non-proliferative tolerogenic pDCs to suppress GVHD, and c) the role of CCR9 itself in tolerance induction. To test the hypothesis that pDCs are uniquely suited to GVHD treatment, the GVHD-suppressing potential of these highly tolerogenic pDCs will be compared to that of a putative tolerogenic myeloid DC population. Graft vs host responses are deleterious when directed at normal host tissues, but can be beneficial in therapeutic anti-tumor (graft vs tumor or GVT) regimens. Regulatory T cells (Tregs) can control systemic GVHD while allowing GVT activity. To test the hypothesis that CCR9+ pDCs can suppress GVHD without abrogating GVT, experiments will be carried out in a mouse leukemia model. Together, these studies will define in detail the potential of CCR9+ pDCs to suppress deleterious effects of GVHD in settings modeling situations in which human patients encounter pathogenic GVHD responses.