Molecular targeting agents in GVHD/GVT: Role of cytokines and T cell subsets

描述（由申请人提供）：异基因造血干细胞移植（HSCT）目前用于治疗各种血液恶性肿瘤。最近，HSCT在实体肿瘤、实体器官移植和自身免疫中的应用重新受到关注。然而，移植物抗宿主病（GVHD）的发生，无论是急性，并随着患病率的增加，慢性形式显着限制了这种方法的使用和疗效。这两种形式的GVHD都是由供体T细胞和细胞因子驱动的。虽然慢性GVHD在HSCT中越来越多地出现，但很少有临床前研究评估其对有益的移植物抗肿瘤（GVT）效应的控制和并发作用。我们和其他人已经表明，细胞因子，如干扰素-γ（IFN？）和TNF-1在GVH/GVT应答中起关键和双重作用。此外，通过蛋白酶体或NFkB抑制的GVHD的分子靶向代表了不仅调节GVHD而且促进GVT的新手段，但是作用机制以及在慢性GVHD中的作用仍然未知。为了建立在我们发表的和初步的数据，我们提出了3个具体的目标来剖析这两种方法的功效和机制-细胞因子操纵和分子靶向。具体目标1将试图剖析IFN？/通过siRNA或抗体阻断的临床可转化方法调节急性GVHD模型中的TNF α/IL-17细胞因子途径。然后，我们将结合联合收割机与分子靶向方法，这些模型，试图进一步控制GVHD病理生物学使用蛋白酶体抑制剂，硼替佐米和一种新的NF κ B抑制剂。然后，具体目标2将确定这些细胞因子在慢性GVHD模型中的作用，观察皮肤和肺病理学，并评估分子靶向在预防和治疗活动性疾病方面的疗效。然后，具体目标3将使用实体和血液癌症模型，并评估这些方法对预防/控制GVHD和潜在促进GVT的有效性。这一建议不应对急性和慢性GVHD产生有价值的见解，但也允许对可翻译方法进行临床前评估，以控制这些方法以及在原位癌症模型中进行评估。 公共卫生相关性：异基因造血干细胞移植（HSCT）目前用于治疗各种血液恶性肿瘤，并且显示出治疗实体癌如肾细胞癌的前景。然而，重大障碍仍然限制了该程序的安全性和有效性。这些并发症中最重要的是移植物抗宿主病（GVHD）和肿瘤复发的发生。该提案将制定临床前策略，以改善同种异体HSCT的应用，从而降低慢性和急性GVHD的发生率和严重程度，并增强移植物抗肿瘤活性，用于治疗实体瘤以及血液系统恶性肿瘤

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (HSCT) is currently used for the treatment of a variety hematologic malignancies. Recently, there has been renewed interest in HSCT for solid cancers as well as solid organ transplantation and autoimmunity. However, the occurrence of graft-versus-host disease (GVHD), in both acute, and with increasing prevalence, chronic forms significantly limits the use and efficacy of this approach. Both forms of GVHD are driven by donor T cells and cytokines. While chronic GVHD has been emerging more and more in HSCT, there have been little preclinical studies assessing its control and concurrent effects on beneficial graft-versus-tumor (GVT) effects. We and others have shown that cytokines such as interferon-gamma (IFN?) and TNF1 play pivotal and dual roles in GVH/GVT responses. Further, molecular targeting of GVHD via proteasome or NFkB inhibition represents a novel means not only modulate GVHD but also promote GVT but mechanisms of action as well as effects in chronic GVHD remain not known. To build on our published and preliminary data we propose 3 Specific Aims to dissect both efficacy and mechanism of these two approaches - cytokine manipulation and molecular targeting. Specific Aim 1 will seek to dissect the roles of the IFN?/TNFa/IL-17 cytokine pathways in acute GVHD models through modulation by clinically translatable approaches by either by siRNA or antibody blockade. We will then combine with molecular targeting approaches to these models in an attempt to further control GVHD pathobiology using the proteasome inhibitor, bortezomib and a novel NFkB inhibitor. Specific Aim 2 will then determine the role of these cytokines in chronic GVHD models looking at skin and lung pathology and assess the efficacy of molecular targeting in not only prevention but also treatment of active disease. Specific Aim 3 will then use both solid and hematologic cancer models and assess the efficacy of these approaches on the prevention/control of GVHD and potential promotion of GVT. This proposal should not shed valuable insights on both acute and chronic GVHD but also allows for preclinical assessment of translatable approaches in their control as well as assessment in orthotopic cancer models. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently used for the treatment of a variety of hematologic malignancies and shows promise for the treatment of solid cancers such as renal cell carcinomas. However, significant obstacles still limit the safety and efficacy of this procedure. Paramount among these complications is the occurrence of graft-versus host disease (GVHD) and tumor relapse. This proposal will develop pre-clinical strategies to improve the application of allogeneic HSCT to reduce the incidence and severity of both chronic and acute GVHD and augment graft versus tumor activity for the treatment of solid tumors as well as hematologic malignancies