Disruption of HLA Class II-Mediated Immune Recognition of B-Cell Lymphomas

HLA II 类介导的 B 细胞淋巴瘤免疫识别的破坏

基本信息

批准号：
7844581
负责人：
Azizul Haque
金额：
$ 1.51万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844581
关键词：
Affect Alleles Amino Acid Sequence Anabolism Antigen Presentation Antigens B-Cell Lymphomas B-Cell Neoplasm B-Lymphocytes Biochemical Biological Biological Process Burkitt Lymphoma CD4 Positive T Lymphocytes CD8B1 gene Cell Line Cells Chromosomal translocation Complementary DNA Complex Cytotoxic T-Lymphocytes Data Defect Dendritic Cells Development Dinoprostone Effector Cell Follicular Lymphoma Foundations Future Gel Goals Helper-Inducer T-Lymphocyte Host Defense Human Herpesvirus 4 Immune Immune response Immunologic Surveillance Incubated Individual Interleukin-10 Interleukin-2 Interleukin-4 Ion Exchange Literature Lymphoma MHC Class II Genes MYC gene Maintenance Malignant - descriptor Malignant lymphoid neoplasm Mass Spectrum Analysis Mediating Molecular Pathway interactions Patients Peptides Precursor B-Lymphoblast Primary Neoplasm Process Production Proteins Proteomics Reaction Sampling Sampling Studies Solid Specificity T-Lymphocyte Testing Time Vascular Endothelial Growth Factors c-myc Genes immunogenic infected B cell leukemia/lymphoma monoclonal antibody production neoplastic cell novel novel strategies public health relevance trait tumor

项目摘要

DESCRIPTION (provided by applicant): Lymphoid malignancies such as lymphoma and leukemia often compromise host defense and have evolved mechanisms to evade immune surveillance. Burkitt lymphoma (BL) is a poorly immunogenic, highly malignant B-cell tumor characterized by chromosomal translocations that constitutively activate the c-myc oncogene. Effective tumor immune responses usually involve the stimulation and maintenance of tumor specific CD8+ HLA class I restricted T effector cells and tumor-specific CD4+ class II restricted T cells. Several groups have shown that BL can not present antigens (Ags) by class I molecules which contribute to their escaping immune recognition from tumor-specific CD8+ T cells. Recently, studies have also shown that HLA class II-restricted CD4+ cytotoxic T cells (CTL) could be generated against BL and as well as non-Hodgkins follicular lymphoma (FL). These studies support the feasibility of using sufficient tumor specific CD4+ T cells to eliminate B-cell tumors. Most B-cell tumors, including BL, express class II molecules, could provide their own MHC class II Ag presentation and be targets for CD4+ T cells. As BL are very poorly immunogenic, we hypothesize that BL and other B-cell lymphomas may also have a defect in stimulation of tumor-specific CD4+ T cells. Our data suggest that CD4+ T cells are unable to recognize Ag in association with HLA class II on BL/FL cells whereas, Epstein Barr Virus (EBV) infected B-cell lymphoblasts (B-LCL) efficiently process and present Ags to T cells in the context of class II molecules. The overall goal of this project is to elucidate the defect(s) in BL/FL responsible for this loss of Ag presentation by HLA class II and to assess whether these identified defect(s) are a global trait of B-cell lymphomas. We will determine the mechanisms for poor class II restricted HLA Ag presentation by BL, FL and other B-cell lymphomas using the following three specific aims: (1) Determine the defective step(s) in Burkitt lymphoma and other B-cell lymphomas that suppress the stimulation of Ag-specific, CD4+ HLA-class II-restricted T cells, (2) Determine mechanisms induced at pH 5.5 that restore the ability of Burkitt lymphoma to stimulate Ag-specific, CD4+ HLA-class II-restricted T cells, and (3) Identify and clone the inhibitory factors shed by Burkitt lymphoma at pH 5.5 that suppress HLA class II-restricted Ag presentation. Cellular, biochemical, molecular, proteomics and functional approaches will be employed to test these aims. These studies will elucidate novel mechanism(s) for restoring Ag presentation to BL cells and for suppressing B-LCL and DC Ag-class II presentation. The elucidated mechanisms will likely spur development of novel strategies to restore CD4+ T cell recognition and clearance of BL and other B-cell lymphomas. PUBLIC HEALTH RELEVANCE: Our studies suggest that there is a defect(s) in HLA class II-mediated immune recognition of B-cell lymphomas, and it likely contributes to tumor cell escape from host defenses. This study will define the defect(s) in B-cell lymphomas responsible for this loss of antigen presentation and CD4+ T cell recognition via HLA class II molecules. The elucidated findings will likely spur development of novel strategies to restore CD4+ T cell recognition and clearance of BL and other B-cell lymphomas.

描述（由申请人提供）：淋巴瘤和白血病等淋巴恶性肿瘤通常会损害宿主防御，并已进化出逃避免疫监视的机制。伯基特淋巴瘤 (BL) 是一种免疫原性差、高度恶性的 B 细胞肿瘤，其特征是染色体易位，组成性激活 c-myc 癌基因。有效的肿瘤免疫反应通常涉及刺激和维持肿瘤特异性CD8+ HLA I类限制性T效应细胞和肿瘤特异性CD4+ II类限制性T细胞。多个研究小组已表明，BL 不能通过 I 类分子呈递抗原 (Ag)，这有助于它们逃避肿瘤特异性 CD8+ T 细胞的免疫识别。最近的研究还表明，可以产生针对 BL 和非霍奇金滤泡性淋巴瘤 (FL) 的 HLA II 类限制性 CD4+ 细胞毒性 T 细胞 (CTL)。这些研究支持使用足够的肿瘤特异性 CD4+ T 细胞来消除 B 细胞肿瘤的可行性。大多数 B 细胞肿瘤（包括 BL）表达 II 类分子，可以提供自己的 MHC II 类 Ag 呈递，并成为 CD4+ T 细胞的靶标。由于 BL 的免疫原性非常差，我们假设 BL 和其他 B 细胞淋巴瘤在刺激肿瘤特异性 CD4+ T 细胞方面也可能存在缺陷。我们的数据表明，CD4+ T 细胞无法识别 BL/FL 细胞上与 HLA II 类相关的 Ag，而 Epstein Barr 病毒 (EBV) 感染的 B 细胞淋巴母细胞 (B-LCL) 可以有效地处理并将 Ag 呈递给 T 细胞。 II 类分子的背景。该项目的总体目标是阐明 BL/FL 中导致 HLA II 类 Ag 呈递丧失的缺陷，并评估这些已识别的缺陷是否是 B 细胞淋巴瘤的整体特征。我们将使用以下三个具体目标确定 BL、FL 和其他 B 细胞淋巴瘤 II 类限制性 HLA Ag 呈递不良的机制：(1) 确定伯基特淋巴瘤和其他 B 细胞淋巴瘤中的缺陷步骤抑制 Ag 特异性、CD4+ HLA-II 类限制性 T 细胞的刺激，(2) 确定在 pH 5.5 下诱导的机制，以恢复伯基特淋巴瘤刺激 Ag 特异性、CD4+ 的能力HLA II 类限制性 T 细胞，以及 (3) 鉴定并克隆伯基特淋巴瘤在 pH 5.5 时释放的抑制因子，这些因子可抑制 HLA II 类限制性 Ag 呈递。将采用细胞、生物化学、分子、蛋白质组学和功能方法来测试这些目标。这些研究将阐明恢复 BL 细胞的 Ag 呈递以及抑制 B-LCL 和 DC II 类 Ag 呈递的新机制。阐明的机制可能会刺激新策略的开发，以恢复 CD4+ T 细胞对 BL 和其他 B 细胞淋巴瘤的识别和清除。公共健康相关性：我们的研究表明，HLA II 类介导的 B 细胞淋巴瘤免疫识别存在缺陷，它可能导致肿瘤细胞逃避宿主防御。这项研究将确定 B 细胞淋巴瘤中导致抗原呈递和 CD4+ T 细胞通过 HLA II 类分子识别丧失的缺陷。阐明的发现可能会刺激新策略的开发，以恢复 CD4+ T 细胞对 BL 和其他 B 细胞淋巴瘤的识别和清除。