Immune Tolerance and Stem Cell Transplantation

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种特殊特征 (CLL)。慢性淋巴细胞性白血病的免疫功能障碍以低丙种球蛋白血症和自身免疫为特征。 现象和感染性并发症是该病发病率和死亡率的主要原因。 该项目之前的工作证明了CLL细胞对T细胞的直接影响，这两种细胞在人类 在这种疾病的EJI-TCL1转基因小鼠模型中，导致acfin变化的样本和 T和NK细胞的聚合及其不能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细胞缺陷是相互作用的结果 CLL细胞与患者免疫系统的关系，这些缺陷的修复将需要最大限度地增加T细胞 体内细胞介导的免疫反应。因此，我们试图确定免疫缺陷的基础。 细胞在CLL中的功能，并修复这些缺陷，为未来的治疗干预。我们将在中研究这一点。 来自CLL患者和E(I-TCL1)转基因小鼠的人类样本。自.以来 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 该计划临床试验中的新药是否对宿主免疫系统有影响，以及 因此很可能会恶化免疫功能。还将开展工作来评估T细胞的性质 介导的ANFI-肿瘤对CLL细胞的免疫应答，并确定这些特异性T细胞应答 发生于同种异体干细胞移植治疗慢性淋巴细胞性白血病。这里的目标是描述 慢性粒细胞白血病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 慢性淋巴细胞性白血病患者T细胞和NK细胞功能障碍及免疫调节药物干预的作用 修补这些缺陷。这里的目标是改善慢性淋巴细胞性白血病患者的免疫功能。第二，评估 银杏叶提取物对Emu-TCLI转基因小鼠CLL体内T细胞缺陷诱导的影响 并评估其对疾病进展的影响。第三，确定移植物抗白血病效应的靶点。 CTN/CALGB 100701中异基因干细胞移植后的CLL。总而言之，这些研究将 评估免疫调节反应对慢性淋巴细胞性白血病的影响。

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.