Immune Tolerance and Stem Cell Transplantation

免疫耐受和干细胞移植

基本信息

批准号：
8235343
负责人：
JOHN G. GRIBBEN
金额：
$ 25.36万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235343
关键词：
Actins Acute Myelocytic Leukemia Address Allogenic Antigen-Presenting Cells Asses Autoimmune Process Cancer and Leukemia Group B Cell physiology Cells Chronic Chronic Lymphocytic Leukemia Clinical Trials Defect Diffuse Large-Cell Lymphoma Disease Disease model Donor Lymphocyte Infusion Emu species Etiology Failure Follicular Lymphoma Functional disorder Future Gene Expression Goals Hematologic Neoplasms Human Immune Immune System Diseases Immune Tolerance Immune response Immune system Immunosuppression Intervention Knowledge Ligands Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Mediating Minor Histocompatibility Antigens Molecular Morbidity - disease rate Multiple Myeloma Natural Killer Cells Nature Patients Pharmaceutical Preparations Prevention Research Residual state Role Sampling Stem cell transplant Stem cells Synapses T cell response T-Lymphocyte Therapeutic Therapeutic Intervention Transgenic Mice Tumor Antigens Vaccination Work alemtuzumab base cancer cell cell mediated immune response conditioning gene function graft vs host disease immune function improved in vivo large cell Diffuse non-Hodgkin&apos s lymphoma lenalidomide leukemia malignant breast neoplasm mortality mouse model neoplastic cell novel polymerization programs purine analog receptor repaired response tumor

项目摘要

PROJECT 4 : Immune Tolerance and Stem Cell Transplantation Impaired immune responses are common in cancer and a particular feature of chronic lymphocyfic leukemia (CLL). The immune dyfuction in CLL is characterised by hypogammaglobulinemia and autoimmune phenomena and infecfious complicafions are a major cause of morbidity and mortality in this disease. Previous work in this Program has demonstrated a direct effect of CLL cells on T cells, both in human samples and in the Eji-TCL1 transgenic mouse model of this disease, that result in changes in acfin polymerizafion in T and NK cells and failure ofthese cells to mount effecfive immune synapses with antigen presenting cells. The central hypothesis of this project Is that specific T cell defects result from interaction of CLL cells with the patient's immune system and that repair of these defects will be required to maximize T cell mediated immune responses in vivo. We therefore seek to characterize the basis for defective immune cell function in CLL and repair these defects for future therapeutic intervenfion. We shall examine this in human samples from pafients with CLL and in an E(i-TCL1 transgenic mouse model of this disease. Since most agents that are used to treat CLL also add to the immune suppression, the project will determine whether novel agents in clinical trials in this Program have impact on the host immune system and are therefore likely to worsen immune funcfion. Work will also be performed to assess the nature of T cell mediated anfi-tumor immune responses against CLL cells and to determine if these specific T cell responses occur following allogeneic stem cell transplantafion for CLL. The goal here is to characterize the nature ofthe graft versus leukemia effect in CLL. To address these issues this project will address the following specific aims: First, to define the molecular mechanism whereby molecules expressed by CLL cells induce dysfunction in T and NK cell in patients with CLL and the role of immunomodulatory drug intervenfion to repair these defects. The goal here is to improve immune funcfion in CLL pafients. Second, to assess the impact of in prevention of induction of T cell defects vivo in the Emu-TCLI transgenic mouse model of CLL and asses its impact on diease progression. Third, to characterize targets of graft versus leukemia effect in CLL after allogeneic stem cell transplantafion in CTN/ CALGB 100701. Taken together, these studies will assess the impact of immune mediated responses in CLL.

项目 4：免疫耐受和干细胞移植免疫反应受损在癌症中很常见，也是慢性淋巴细胞白血病的一个特殊特征（CLL）。 CLL 的免疫功能障碍以低丙种球蛋白血症和自身免疫性疾病为特征现象和感染性并发症是该疾病发病和死亡的主要原因。该项目之前的工作已经证明了 CLL 细胞对 T 细胞的直接影响，无论是在人类还是在 T 细胞上。样本和该疾病的 Eji-TCL1 转基因小鼠模型中，导致 acfin 发生变化 T 细胞和 NK 细胞中的聚合以及这些细胞无法与抗原建立有效的免疫突触呈现细胞。该项目的中心假设是特定的 T 细胞缺陷是由相互作用引起的 CLL 细胞与患者免疫系统的相互作用，并且需要修复这些缺陷才能最大限度地提高 T 体内细胞介导的免疫反应。因此，我们试图描述免疫缺陷的基础 CLL 中的细胞功能并修复这些缺陷以用于未来的治疗干预。我们将在来自 CLL 患者和该疾病的 E(i-TCL1 转基因小鼠模型) 的人类样本。大多数用于治疗 CLL 的药物也会增加免疫抑制，该项目将确定本计划临床试验中的新药是否对宿主免疫系统有影响？因此可能会恶化免疫功能。还将开展评估 T 细胞性质的工作介导针对 CLL 细胞的抗肿瘤免疫反应，并确定这些特异性 T 细胞反应是否发生在 CLL 的同种异体干细胞移植后。这里的目标是描述事物的本质 CLL 中的移植物抗白血病效应。为了解决这些问题，该项目将解决以下具体问题目的：首先，明确 CLL 细胞表达的分子诱导 CLL患者T细胞和NK细胞功能障碍及免疫调节药物干预的作用修复这些缺陷。这里的目标是改善 CLL 患者的免疫功能。其次，评估在 CLL 的 Emu-TCLI 转基因小鼠模型中预防体内诱导 T 细胞缺陷的影响并评估其对疾病进展的影响。第三，表征移植物抗白血病效应的靶点 CTN/CALGB 100701 中同种异体干细胞移植后的 CLL。总而言之，这些研究将评估免疫介导反应对 CLL 的影响。