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

GVHD/GVT 中的分子靶向药物：细胞因子和 T 细胞亚群的作用

基本信息

批准号：
7740729
负责人：
WILLIAM JOSEPH MURPHY
金额：
$ 27.57万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7740729
关键词：
Acute Acute Graft Versus Host Disease Address Affect Allogenic Antibodies Autoimmune Diseases Autoimmunity B-Lymphocytes Bortezomib CD4 Positive T Lymphocytes CD8B1 gene Cancer Model Cellular Structures Chronic Clinical Data Data Disease Disease model Engraftment Generations Graft-Versus-Tumor Induction Hematologic Neoplasms Hematopoietic Hematopoietic Stem Cell Transplantation Homing Immune Incidence Inflammation Mediators Inflammatory Interferon Type II Interferons Learning Lung Malignant Neoplasms Mediating Modality Modeling Molecular Target Morbidity - disease rate Mus Myelogenous Nature Organ Transplantation Pathology Pathway interactions Plasma Cells Play Prevalence Prevention Procedures Process Production Proteasome Inhibition Proteasome Inhibitor Publishing Relapse Renal Cell Carcinoma Reporting Role Safety Severities Severity of illness Signal Transduction Skin Small Interfering RNA Solid Solid Neoplasm T-Lymphocyte T-Lymphocyte Subsets TNF gene Toxic effect Transplantation active method base cancer cell chronic graft versus host disease clinical application cytokine graft vs host disease improved inhibitor/antagonist insight interest multicatalytic endopeptidase complex novel pre-clinical preclinical study prevent public health relevance receptor response small molecule success tumor

项目摘要

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

描述（由申请人提供）：同种异体造血干细胞移植（HSCT）目前用于治疗多样性血液学恶性肿瘤。最近，人们对固体癌症以及固体器官移植和自身免疫的HSCT引起了人们的兴趣。然而，急性疾病（GVHD）的发生，并且随着患病率的增加，慢性形式显着限制了这种方法的使用和功效。两种形式的GVHD均由供体T细胞和细胞因子驱动。虽然慢性GVHD在HSCT中越来越多，但几乎没有临床前研究评估其对有益的移植物及其效果（GVT）效应的控制和同时影响。我们和其他人表明，诸如干扰素 - 伽马（IFN？）和TNF1之类的细胞因子在GVH/GVT响应中起关键和双重作用。此外，通过蛋白酶体或NFKB抑制GVHD的分子靶向不仅代表了一种新颖的手段，不仅可以调节GVHD，还可以促进GVT，还可以促进GVT，还可以促进慢性GVHD的作用机理以及效果。为了建立我们已发表的初步数据，我们提出了3个特定目的，旨在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将寻求探索急性GVHD模型中IFN？/TNFA/IL-17细胞因子途径的作用，该途径通过siRNA或抗体阻滞的临床可翻译方法调节。然后，我们将与这些模型的分子靶向方法结合使用，以尝试使用蛋白酶体抑制剂，硼替佐米和一种新型的NFKB抑制剂来进一步控制GVHD病理生物学。然后，特定的目标2将确定这些细胞因子在慢性GVHD模型中的作用，这些模型看着皮肤和肺病理学，并评估分子靶向不仅在预防方面，而且还治疗活性疾病的疗效。然后，特定的目标3将使用固体和血液学癌症模型，并评估这些方法对预防/控制GVHD的疗效和GVT的潜在促进。该提案不应对急性和慢性GVHD提供有价值的见解，而应允许对其控制中的可翻译方法进行临床前评估以及原位癌模型中的评估。公共卫生相关性：同种异体造血干细胞移植（HSCT）目前用于治疗多种血液系统恶性肿瘤，并显示出对治疗固体癌症（如肾细胞癌）治疗的希望。但是，重大障碍仍然限制了此程序的安全性和功效。这些并发症中最重要的是发生移植物抗宿主疾病（GVHD）和肿瘤复发。该建议将制定临床前策略，以改善同种异体HSCT的应用，以降低慢性和急性GVHD的发生率和严重程度，以及增强移植物与肿瘤活性以治疗实体瘤以及血液学恶性肿瘤