Augmentation of Anti-Tumor Activity in the Absence of B Cells

在没有 B 细胞的情况下增强抗肿瘤活性

• 批准号: 7226411
• 负责人: Joseph David Rosenblatt
• 金额: $ 23.58万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226411
• 关键词: Address; Adoptive Transfer; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; B-Cell Activation; B-Lymphocytes; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Vaccines; Cell Lineage; Cells; Chimeric Proteins; Condition; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Effectiveness; Effector Cell; Environment; Exhibits; Gene Transfer; Goals; Growth; Hen Egg Lysozyme; Human; IL2RA gene; Immune; Immune response; Immunity; Immunization; Immunocompetent; Immunoglobulin M; Implant; In Vitro; Infiltration; Interleukin-10; Intervention; Lead; Lymphoid; MS4A1 gene; Malignant Neoplasms; Mediating; Modeling; Monoclonal Antibodies; Mus; Nature; Ovalbumin; Pattern; Phase; Play; Primary Neoplasm; Property; Relative (related person); Resistance; Role; Spleen; T-Lymphocyte; TNFRSF5 gene; TNFSF4 gene; Testing; Transgenic Mice; Transgenic Organisms; Transplantation; Tumor Immunity; base; cytokine; design; implantation; in vivo; irradiation; lymph nodes; man; model development; mouse model; neoplastic cell; receptor; reconstitution; research study; response; rituximab; tositumomab; tumor; tumor growth; tumor necrosis factor ligand superfamily member 4

j < Cytolytic T cell (CTL) and Th1 responses are important effector mechanisms in anti-tumor immunity. Little is known about role of B cells in regulating anti-tumor responses. IgM"'" B cell-deficient mice (BCDM) exhibit enhanced resistance to primary tumors compared to immunocompetent mice (ICM). Two of three syngeneic tumors (EL4 and MC38) regress spontaneously in BCDM while growth of a third (B16) was markedly slowed. Enhanced anti-tumor resistance of BCDM was associated with increased T cell infiltration, enhanced Th1 cytokine response and increased CTL activity. Reconstitution of BCDM with wild type but not OX40L"7"B cells results in decreased tumor resistance. The absence of B cells may result in enhanced Th1 and CTL responses to tumors. The overall goal of this proposal is to understand mechanisms leading to an enhanced anti-tumor response in the absence of B cells, and determine whether the proactive depletion of B cells in normal hosts will replicate conditions leading to an enhanced response. In Aim /we will study the anti-tumor T cell responses seen in ICM and BCDM and delineate the T-cell responses involved in augmentation of tumor resistance by depletion of lymphoid subsets and/or adoptive transfer experiments. The potential role of CD4+ CD25+ T regulatory cells will also be investigated. In Aim II, we will examine the immunoregulatory mechanisms underlying inhibition of anti-tumor immunity by B cells. We will study the effects of reconstitution with wild type and OX40L"'" B cells on expansion and differentiation of tumor specific CD4+ and CD8+ T cells and anti-tumor response in BCDM. We will identify B cell effector subsets that may play a role in inhibiting anti-tumor responses. We will determine whether additional candidate B cell-derived factors or receptors such CD40, IL-10, and TGF-3 may play a role in inhibiting anti- tumor immunity. We will examine whether antigen presenting cells (dendritic cells) in BCDM have altered properties that may lead to the enhanced tumor immunity. In Aim III, we will develop murine models for pro- active B cell depletion and study the effect of B cell depletion on anti-tumor immune responses, alone or in combination with other immune intervention strategies such as cytokine delivery, gene transfer, and/or adoptive T cell transfer. Effects of B cell depletion using Rituximab and additional agents will be modeled in a human CD20-BAC transgenic mouse which mimics normal patterns of CD20 expression in B cells. We will test direct B cell depletion or depletion following transplant of huCD20-BAC transgenic bone marrow into irradiated host mice. Since B cells can be efficiently and safely depleted in man using monoclonal antibodies such asRituximab, strategies developed in Aim III canreadily be applied to design of human Phase l/ll trials.

j < 溶细胞 T 细胞 (CTL) 和 Th1 反应是抗肿瘤免疫的重要效应机制。小的是 已知 B 细胞在调节抗肿瘤反应中的作用。 IgM"'" B 细胞缺陷小鼠 (BCDM) 表现出 与免疫活性小鼠（ICM）相比，对原发性肿瘤的抵抗力增强。三个同基因中的两个 BCDM 中的肿瘤（EL4 和 MC38）会自发消退，而第三种肿瘤（B16）的生长则明显减慢。 BCDM 增强的抗肿瘤抵抗力与 T 细胞浸润增加、Th1 增强相关 细胞因子反应和 CTL 活性增加。用野生型而非 OX40L"7"B 重建 BCDM 细胞导致肿瘤抵抗力下降。 B 细胞的缺乏可能导致 Th1 和 CTL 增强 对肿瘤的反应。 该提案的总体目标是了解增强抗肿瘤作用的机制 在没有 B 细胞的情况下做出反应，并确定 B 细胞是否主动耗尽 正常宿主会复制导致增强响应的条件。 在 Aim 中，我们将研究 ICM 和 BCDM 中观察到的抗肿瘤 T 细胞反应，并描绘 T 细胞 通过消除淋巴亚群和/或过继来增强肿瘤抵抗力的反应 转移实验。 CD4+ CD25+ T 调节细胞的潜在作用也将得到研究。在目标二中， 我们将研究 B 细胞抑制抗肿瘤免疫的免疫调节机制。 我们将研究野生型和 OX40L"'" B 细胞重建对扩增和分化的影响 BCDM 中肿瘤特异性 CD4+ 和 CD8+ T 细胞的变化以及抗肿瘤反应。我们将鉴定 B 细胞效应子 可能在抑制抗肿瘤反应中发挥作用的亚群。我们将决定是否额外 候选 B 细胞衍生因子或受体，如 CD40、IL-10 和 TGF-3 可能在抑制抗- 肿瘤免疫。我们将检查BCDM中的抗原呈递细胞（树突状细胞）是否发生了改变 可能导致增强肿瘤免疫力的特性。在目标 III 中，我们将开发小鼠模型 主动 B 细胞耗竭并研究 B 细胞耗竭对抗肿瘤免疫反应的影响，单独或联合使用 与其他免疫干预策略相结合，例如细胞因子递送、基因转移和/或 过继性 T 细胞转移。使用 Rituximab 和其他药物消除 B 细胞的效果将在 人 CD20-BAC 转基因小鼠模仿 B 细胞中 CD20 表达的正常模式。我们将 测试直接 B 细胞耗竭或 huCD20-BAC 转基因骨髓移植后的耗竭 受辐射的宿主小鼠。由于使用单克隆抗体可以有效、安全地消除人体 B 细胞 例如利妥昔单抗，Aim III 中开发的策略可以很容易地应用于人体 l/ll 期试验的设计。