(PQB3) CD4 T cell response to BCR-ABL-positive Leukemia

(PQB3) CD4 T 细胞对 BCR-ABL 阳性白血病的反应

• 批准号: 9262063
• 负责人: Michael Archibald Farrar
• 金额: $ 31.23万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262063
• 关键词: Address; Amino Acids; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; Applications Grants; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Bone Marrow Transplantation; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Death; Cell Lineage; Cells; Chimeric Proteins; Chromosomal translocation; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 9; Chronic Myeloid Leukemia; Complex; Contrast Media; Data; Defect; Development; Effectiveness; Effector Cell; Engineering; Epitopes; Failure; Generations; Goals; Grant; Growth; HLA-DR4 Antigen; Histocompatibility Antigens Class II; Human; Imatinib; Immune; Immune response; Immune system; Immunity; Immunization; Immunotherapy; Interferon Type II; Kinetics; Knowledge; Leukemic Cell; Ligands; MHC Class II Genes; Measures; Methods; Monitor; Mus; Oncogenes; Outcome; Patient-Focused Outcomes; Patients; Peptides; Phenotype; Play; Preventive vaccine; Proteins; Reagent; Refractory; Regulatory T-Lymphocyte; Residual Neoplasm; Role; T cell response; T-Lymphocyte; TNFRSF10A gene; Testing; Th2 Cells; Time; Translations; Tyrosine Kinase Inhibitor; anergy; base; bcr-abl Fusion Proteins; cytokine; cytotoxic; effective therapy; in vivo; inhibitor/antagonist; leukemia; mouse model; novel; novel strategies; premature; prevent; public health relevance; receptor; resistance mutation; response; small molecule; tumor

DESCRIPTION (provided by applicant): Translocations between chromosomes 9 and 22 result in the generation of the novel fusion protein that is a critical oncogene in both chronic myelogenous leukemia (CML) and B cell acute lymphoblastic leukemia (B-ALL). The use of tyrosine kinase inhibitors (TKIs), such as imatinib that targets the BCR-ABL fusion protein, has proven to be extremely successful in patients with CML. In contrast, TKIs have not been very effective in treating patients with B-ALL, largely due to the acquisition of resistance mutations that render the inhibitors non-functional. Since the BCR-ABL fusion generates a foreign antigen that can be seen by the immune system, an alternative approach to treating BCR-ABL+ ALL involves immunotherapy. The potential efficacy of such an approach is suggested by a subset of BCR-ABL+ B-ALL patients with very low levels of minimal residual disease (MRD). Low MRD is associated with patients that have BCR-ABL-specific T cells that make interferon-gamma; loss of these T cells correlates with an increase in MRD and poor patient outcome. Likewise, in a mouse model of BCR-ABL+ B-ALL, we have observed that T cells exist that can mount robust immune responses to the BCR-ABL fusion peptide. A key question is why such T cells in both mice and humans typically do not eliminate BCR-ABL+ leukemic cells. This has been a difficult question to answer because previous studies have not been able to examine the endogenous T cell response to the BCR-ABL peptide. To address this issue this project will track the CD4+ T cell response to BCR-ABL-induced B-ALL using MHC Class II: peptide tetramers. These tetramers are composed of a 13 amino acid peptide that spans the e1a2 BCR-ABL breakpoint bound to I-Ab (BAp:I-Ab), which is the MHCII molecule in C57BL/6 mice. This novel reagent will allow us to determine the number of BAp:I-Ab-specific T cells in a naive mouse and establish how well these cells expand following strong immunization with the BAp peptide or following initiation of BCR- ABL+ leukemia. This approach will allow us to determine whether the failure of BAp:I-Ab specific T cells to eliminate BCR-ABL+ cells is due to a defect in antigen presentation, induction of anergy, deletion of BAp:I-Ab- specific cells or immune deviation (i.e., differentiatio into Treg, TFH or TH2 cell lineages). Based on these findings we will then pursue a variety of strategies to enhance BAp:I-Ab-specific immune responses. Our hypothesis is that generating CD4+ T cells with cytolytic activity will be critical for inducing effective T cell immunity to BCR ABL+ B-ALL. Finally, to enhance the translational potential of my findings we will generate BAp:DR4 tetramers that will allow us to track similar anti-leukemia responses in mice expressing human DR4 (B6.DR4 mice). The results of these studies could then be directly applied to human patients as the BAp:DR4 tetramer could be used to track BAp-specific T cell in patients with BCR-ABL that are DR4+ or that receive a DR4+ bone marrow transplant.

描述（由申请人提供）：染色体9和22之间的易位导致新型融合蛋白的产生，这是慢性粒细胞性白血病（CML）和B细胞急性淋巴细胞性白血病（B-all）的关键癌基因。在CML患者中，使用酪氨酸激酶抑制剂（TKIS）（例如针对BCR-ABL融合蛋白的伊马替尼）非常成功。相比之下，TKI在治疗B-all的患者方面并不是很有效，这主要是由于获得了使抑制剂非功能性的抗性突变。由于BCR-ABL融合会产生一种外国抗原，可以通过免疫系统看到，因此治疗BCR-ABL+的另一种方法都涉及免疫疗法。这种方法的潜在疗效是由BCR-ABL+ B-ALL患者的一部分提出的，这些患者具有极低的残留疾病（MRD）。低MRD与具有干扰素γ的BCR-燃烧特异性T细胞的患者有关。这些T细胞的丢失与MRD和患者预后差的增加有关。同样，在BCR-ABL+ B-ALL的小鼠模型中，我们观察到存在T细胞可以安装对BCR-ABL融合肽的强大免疫反应。一个关键的问题是，为什么小鼠和人类中的这种T细胞通常不会消除BCR-ABL+白血病细胞。这是一个很难回答的问题，因为以前的研究无法检查内源性T细胞对BCR-ABL肽的反应。为了解决此问题，该项目将使用MHC II类：肽四聚体跟踪CD4+ T细胞对BCR-ABL诱导的B-all的响应。这些四聚体由13个氨基酸肽组成，该氨基酸肽跨越了与I-AB（BAP：I-AB）结合的E1A2 BCR-ABL断裂点，该氨基酸肽是C57BL/6小鼠中的MHCII分子。这项新型试剂将使我们能够确定幼稚小鼠中的BAP的数量：I-AB特异性T细胞，并确定这些细胞在用BAP肽或BCR-ABL+白血病开始后强烈免疫后的膨胀程度。这种方法将使我们能够确定BAP：I-AB特异性T细胞消除BCR-ABL+细胞的失败是由于抗原表现中的缺陷，诱导厌食，BAP缺失：I-AB-特异性细胞或免疫偏差（即，在Treg，TREG，TFH或TH2细胞线索中分开）。基于这些发现，我们将采取各种策略来增强BAP：I-AB特异性免疫反应。我们的假设是，产生具有胞溶活性的CD4+ T细胞对于诱导有效的T细胞免疫至关重要 abl+ b-all。最后，为了增强我的发现的翻译潜力，我们将生成BAP：DR4四聚体，这将使我们能够跟踪表达人DR4（B6.DR4小鼠）的小鼠中相似的抗白血病反应。然后可以将这些研究的结果直接应用于人类患者，因为BAP：DR4四聚体可用于跟踪DR4+的BCR-ABL患者的BAP特异性T细胞，或者接受DR4+骨髓移植。