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

描述(申请人提供)：异基因造血干细胞移植(HSCT)目前用于治疗多种恶性血液病。最近，人们对HSCT治疗实体肿瘤以及实体器官移植和自身免疫重新产生了兴趣。然而，移植物抗宿主病(GVHD)的发生，无论是急性的，还是随着发病率的增加，慢性形式都极大地限制了这一方法的使用和效果。这两种类型的移植物抗宿主病都是由供体T细胞和细胞因子驱动的。虽然慢性移植物抗宿主病越来越多地出现在造血干细胞移植中，但很少有临床前研究评估其控制和同时对有益的移植物抗肿瘤(GVT)效应的影响。我们和其他人已经证明，细胞因子，如干扰素-伽马(干扰素？)而TNF1在GVH/GVT反应中起着举足轻重的双重作用。此外，通过抑制蛋白酶体或抑制NFkB来靶向GVHD是一种新的手段，不仅可以调节GVHD，还可以促进GVT，但其作用机制和对慢性GVHD的影响尚不清楚。基于我们已发表的和初步的数据，我们提出了三个具体目标来剖析这两种方法的有效性和机制-细胞因子操纵和分子靶向。具体目标1旨在通过siRNA或抗体阻断等临床可翻译途径的调节，剖析干扰素？/肿瘤坏死因子/白介素17细胞因子通路在急性移植物抗宿主病模型中的作用。然后，我们将结合分子靶向方法来研究这些模型，试图使用蛋白酶体抑制剂bortezomib和一种新的NFkB抑制剂进一步控制GVHD的病理生物学。具体目标2将确定这些细胞因子在慢性移植物抗宿主病模型中的作用，观察皮肤和肺的病理，并评估分子靶向不仅在预防而且在治疗活动性疾病方面的效果。然后，具体目标3将使用实体和血液学癌症模型，并评估这些方法在预防/控制GVHD和潜在促进GVT方面的效果。这项建议不应在急性和慢性GVHD方面提供有价值的见解，但也允许对其控制下的可翻译方法进行临床前评估，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)目前被用于治疗各种恶性血液疾病，并显示出治疗实体癌(如肾癌)的前景。然而，严重的障碍仍然限制了这一手术的安全性和有效性。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。这项建议将开发临床前策略，以改进异基因造血干细胞移植的应用，以降低慢性和急性移植物抗宿主病的发生率和严重性，并增强移植物抗肿瘤活性，用于实体瘤和血液系统恶性肿瘤的治疗。

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