Cytotoxic-T-Lymphocyte (CTL) Therapy of AML

AML 的细胞毒性 T 淋巴细胞 (CTL) 疗法

• 批准号: 8588898
• 负责人: Bruce R Blazar
• 金额: $ 28.53万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588898
• 关键词: AIDS/HIV problem; Accounting; Acute Myelocytic Leukemia; Acute leukemia; Allogeneic Bone Marrow Transplantation; Allogenic; Allogenicity; Antigen-Presenting Cells; Architecture; B-Lymphocytes; Binding; Bone Marrow Transplantation; CCL19 gene; CCL21 gene; CXCL13 gene; Cells; Cytotoxic T-Lymphocytes; Data; Defect; Dendritic Cell Vaccine; Dendritic Cells; Disease remission; Donor Lymphocyte Infusion; Emigrant; Failure; Fc Receptor; Fibrosis; HIV; Helper-Inducer T-Lymphocyte; Hematopoietic; Immune; Immune response; Immune system; Infection; Infusion procedures; Injury; Listeria monocytogenes; Lymphocyte; Lymphoid; Lymphoid Tissue; Mediating; Memory; Murid herpesvirus 1; Mycoses; Natural regeneration; Nature; Organ; Organogenesis; Patients; Procedures; Process; Radiation; Recovery; Recurrence; Regimen; Relapse; Relative (related person); Risk; Signal Transduction; Stromal Cells; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transplant Recipients; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; Tumorigenicity; Up-Regulation; Vesicular stomatitis Indiana virus; Virus; Virus Diseases; age effect; aged; chemokine; conditioning; disorder risk; exhaust; graft vs host disease; human CXCL13 protein; immune function; improved; injured; lymph nodes; member; neoplastic cell; novel; pathogen; prevent; public health relevance; receptor; repaired; response; restoration; tumor

DESCRIPTION (provided by applicant): Allogeneic bone marrow transplantation (BMT) can cure patients with risk acute myeloid leukemia (AML). Post-BMT recipients are highly susceptible to T cell responsive viral and fungal infections. We discovered that the BMT procedure itself was critical to the failure to cure AML. The fundamental realization was that the conditioning injured host secondary lymphoid organs. Key findings late post-BMT include: 1. Small lymph nodes (LNs) and disorganized microarchitecture; 2. Low numbers of recent thymic emigrants and endogenously generated T cells, even at times late post-BMT, that localized to LNs where they receive the necessary signals to persist; 3. Markedly diminished expression of T- and B-cell chemokines (CCL19, 21, CXCL13) and LN stromal cells depletion; 4. Adenoviral CCL21 transduced dendritic cell vaccines or agonistic anti-lymphotoxin receptor (LT¿R) mAb given to BMT recipients mediated restoration of CCL21 expression, improved LN architecture, increased LN size and T cell content, and augmented the endogenous immune response to pathogen, virus or AML challenge. These data led to our unifying and novel hypothesis that conditioning regimen-induced LN stromal injury is a major impediment to T cell and B cell immune system recovery post-BMT, predisposing the recipient to succumb to infections with pathogens and tumor recurrence. LN organogenesis is dependent upon lymphotoxin-¿1¿2, expressed on activated T-cells, B-cells and lymphoid tissue inducer cells, binding to LN stromal cells. Since there is a profound reduction in na¿ve T- and B-cells and lymphoid tissue inducer cells in the LN late post-BMT, insufficient lymphotoxin signals are available, stromal derived T- and B-cell chemoattractants are not produced, and the LN is inadequate to support T cell priming and survival. We hypothesize that T cell mislocalization may substantially contribute to post-BMT immune deficiency. Our aims are to test the hypothesis that: 1. Chemokines and lymphotoxin-¿ signals to regenerate LN stroma will facilitate T-cell recruitment into and within the LN. Hypothesis: LN stroma regeneration will increase immune function. Chemokine upregulation and lymphotoxin-¿ signals will be evaluated for LN repair and graft-versus-host disease (GVHD) risk under conditions that cause different degrees of LN stromal injury due to effects of age, conditioning and allogenicity. LN regeneration strategies will include: dendritic cell delivery of CCL21 or CXCL13 chemokines, LT¿/¿ signals via agonistic anti-LT¿R mAb or lymphoid tissue inducer cell infusion; and 2. Regenerating the LN stroma will augment T cell responses to AML, pathogen(s) and viruses without increasing GVHD. Hypothesis: Augmented recovery of endogenous immune function by regenerating LN stroma post-BMT leads to greater clearance of AML, pathogens and viruses. Challenge of post-BMT recipients with Listeria monocytogenes, vesicular stomatitis virus or murine cytomegalovirus will be used to assess na¿ve and effector/memory responses to pathogens in BMT recipients after LN regeneration.

描述（由申请人提供）：同种异体骨髓移植 (BMT) 可以治愈患有急性髓系白血病 (AML) 的患者，BMT 后的受者对 T 细胞反应性病毒和真菌感染高度敏感。未能治愈 AML 的关键是，BMT 后后期的主要发现包括： 1. 小淋巴结 (LN) 和紊乱。微结构；2. 近期胸腺迁移和内源性生成的 T 细胞数量较少，甚至在 BMT 后期也如此，它们定位于 LN，在那里它们接收必要的信号以持续存在；3. T 细胞和 B 细胞趋化因子的表达显着减少。 (CCL19、21、CXCL13)和LN基质细胞耗竭；4.腺病毒CCL21转导的树突状细胞疫苗；给予 BMT 接受者的激动性抗淋巴毒素受体 (LT¿R) mAb 介导 CCL21 表达的恢复，改善 LN 结构，增加 LN 大小和 T 细胞含量，并增强对病原体、病毒或 AML 攻击的内源性免疫反应。导致我们统一且新颖的假设，即预处理方案引起的 LN 基质损伤是 BMT 后 T 细胞和 B 细胞免疫系统恢复的主要障碍，使受者容易出现死于病原体感染和肿瘤复发取决于淋巴毒素-¿ 1¿2，在活化的 T 细胞、B 细胞和淋巴组织诱导细胞上表达，与 LN 基质细胞结合，因为在活化的 T 细胞、B 细胞和淋巴组织上表达的 na¿2 显着减少。诱导细胞，与 LN 基质细胞结合。 BMT 后期 LN 中存在 T 细胞和 B 细胞以及淋巴组织诱导细胞，可用的淋巴毒素信号不足，不会产生基质衍生的 T 细胞和 B 细胞趋化物，并且 LN 不足以支持 T 细胞启动和我们认为 T 细胞错误定位可能会导致 BMT 后免疫缺陷，我们的目的是检验以下假设： 1. 趋化因子和淋巴毒素-¿再生 LN 基质的信号将促进 T 细胞募集到 LN 中和内部。 假设：LN 基质再生将增强趋化因子上调和淋巴毒素。由于年龄、条件和同种异体性的影响，导致不同程度的 LN 基质损伤的情况下，将评估信号的 LN 修复和移植物抗宿主病 (GVHD) 风险，包括：树突状细胞递送 CCL21 或。 CXCL13 趋化因子，LT¿ /¿通过激动性抗 LT 发出信号¿ R mAb 或淋巴组织诱导细胞输注；以及 2. 再生 LN 基质将增强 T 细胞对 AML、病原体和病毒的反应，而不增加 GVHD 假设：通过 BMT 后再生 LN 基质来增强内源性免疫功能的恢复。更好地清除 AML、病原体和病毒。巨细胞病毒将用于评估 na¿ LN 再生后 BMT 受者对病原体的效应/记忆反应。