Targeting CC-Chemokine Receptor 7 for the prevention of graft-versus-host disease

靶向 CC-趋化因子受体 7 预防移植物抗宿主病

• 批准号: 8224351
• 负责人: JAMES M COGHILL
• 金额: $ 13.23万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8224351
• 关键词: Accounting; Address; Adverse effects; Allogenic; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Attenuated; Biological Assay; Biology; Blocking Antibodies; Blood; Bone Marrow; CC chemokine receptor 7; CCL19 gene; CCL21 gene; Cell Adhesion Molecules; Cell Line; Cell Surface Receptors; Cell physiology; Cells; Cellular biology; Chemicals; Chemotaxis; Clinical; Collaborations; Collection; Color; Complication; Data; Dendritic Cells; Development; Diarrhea; Disease; Disease model; Donor person; Dose; Drug resistance; Drug usage; Effectiveness; Effector Cell; Environment; Exanthema; Exhibits; Funding; Future; Generations; Goals; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; High Dose Chemotherapy; Human; Immune; Immune response; Immunology; Immunosuppressive Agents; In Vitro; Inflammatory; Infusion procedures; Injury; Instruction; K-Series Research Career Programs; Knock-out; Laboratories; Lead; Learning; Ligands; Liver; Lymphatic; Lymphocyte; Lymphocyte Homing Receptors; Lymphoid; Lymphoid Tissue; Major Histocompatibility Complex; Malignant - descriptor; Malignant Neoplasms; Mediating; Mentors; Modality; Modeling; Movement; Mus; Nature; Non-Malignant; Normal Cell; Organ; Outcome; Pathogenesis; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Play; Population; Prevention; Principal Investigator; Process; Property; Protein Kinase; Publishing; Radiation; Reaction; Regimen; Regulatory T-Lymphocyte; Reporter; Research Personnel; Residual Cancers; Role; Running; Secondary to; Siblings; Signal Transduction; Site; Specificity; Spleen; Staging; Stem cell transplant; Stem cells; Steroids; Structure; System; T-Lymphocyte; Therapeutic; Therapeutic procedure; Tissues; Toxic effect; Transplant Recipients; Transplantation; United States National Institutes of Health; Work; base; chemokine receptor; chemotherapy; conditioning; design; didactic education; disorder prevention; drug candidate; drug development; drug discovery; experience; genetically modified cells; graft vs host disease; high throughput screening; human stem cells; immunoregulation; in vivo; irradiation; knockout animal; leukemia; lymph nodes; novel; novel strategies; oncology; prevent; receptor; response; responsible research conduct; skills; small molecule; trafficking; tumor

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (HSCT) is a therapeutic procedure that is used to treat advanced hematologic malignancies or other blood disorders. HSCT involves the administration of chemotherapy and/or radiation to patients, followed by the transplant of hematopoietic stem cells from a sibling or unrelated matched donor. Because transplant recipients are "rescued" from the bone marrow suppressing effects of the pre-transplant conditioning regimen by the subsequent infusion of healthy stem cells, very high doses of chemotherapy can be administered in an effort to overcome any drug resistance displayed by the malignancy. In addition, mature donor cells present in the stem cell product can mount potent immune responses against any residual cancer that might still be present. Unfortunately, however, these immune reactions are not specific for diseased cells, and normal host tissues can be damaged as well. This process is referred to as graft-versus-host disease (GVHD), and can result in a severe skin rash, profound diarrhea, or liver injury. GVHD is most often treated with high doses of steroids, a therapy that is not always effective and associated with substantial side effects. As a result, laboratories are actively exploring new approaches for treating this difficult disorder. Recently Dr. Coghill, the principal investigatorof the present proposal, published animal model data showing that donor cells lacking the lymph node trafficking receptor CC-Chemokine receptor 7 (CCR7) generate greatly attenuated GVHD responses when transplanted into recipient mice. Cells without CCR7 failed to traffic normally to recipient lymph nodes, and demonstrated a reduced capacity to expand within the spleen. Importantly, however, donor cells lacking CCR7 were able to mount potent anti-cancer immune effects after transplant, and donor regulatory T cells (a population of anti-inflammatory cells) were able to prevent GVHD in the absence of CCR7. Collectively, these findings indicated that blocking the function of CCR7 might prove to be a new and effective approach for preventing GVHD without inhibiting beneficial anti-cancer effects or interfering with the ability of donor regulatory T cells to down-regulate overly aggressive immune responses. There are currently no drugs that block the function of CCR7 that are available for use in HSCT patients or for study in animal models. As a result, this proposal describes a strategy for developing antagonists against CCR7. For this work, we will use genetically engineered cell lines which generate a color signal in the presence of the natural ligands for CCR7: CCL19 and CCL21. With these cells, we will robotically screen a collection of approximately 120,000 small molecules for agents with CCR7 antagonist properties, looking for compounds that are able to block color generation in our primary reporter assay. Actives from the primary screen would then be assessed for cellular toxicity and for specificity against CCR7. Lead compounds would next be evaluated for functionality by assessing their ability to impair chemotaxis (cellular movement) in vitro, a process that is mediated by CCR7. Ultimately, promising compounds would be evaluated for efficacy in vivo by examining their capacity to inhibit GVHD in mouse transplant models. While beyond the scope of the present proposal, lead compounds could be continually refined using medicinal chemistry approaches to maximize their potency and selectivity against CCR7, and developed into drugs for use in human patients undergoing stem cell transplantation. In addition to this CCR7 antagonist discovery effort, mechanistic studies are described to better understand how donor regulatory T cells function after HSCT without CCR7, as previous studies had suggested a critical role for this receptor in their normal function. This proposal is being submitted for a K08 mentored career development award. As a result, the project is designed to provide a substantial educational component for the principal investigator in addition to accomplishing its specific scientific objectives. Dr. Coghill's long-trm goal is to run his own laboratory, with a focus on GVHD pathogenesis and the use of novel, small molecule therapeutics for its treatment and/or prevention. While possessing a strong background in hematology and oncology, this work will offer Dr. Coghill an opportunity to receive additional in-depth instruction in immunology, cell signaling, and the early phases of drug discovery. Dr. Coghill will learn first-hand from an expert mentoring team led by Drs. Jonathan Serody and Stephen Frye, world experts in the fields of lymphocyte trafficking and drug development respectively. A formalized didactic curriculum is also proposed, including coursework in pharmacology, cell biology, grantsmanship, and the responsible conduct of research. Through these experiences, Dr. Coghill will obtain the skills necessary to transition to an independent, NIH funded laboratory investigator. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic stem cell transplantation is a therapeutic modality that is used to treat advanced blood related cancers or other hematologic disorders. Its effectiveness is greatly limited, however, by graft-versus-host disease (GVHD), a process by which donor immune cells attack normal recipient tissues. This proposal details the early development phases of a candidate drug directed against the lymph node homing receptor CC-Chemokine receptor 7 (CCR7) that might ultimately be used to prevent GVHD in human stem cell transplant patients.

描述（由申请人提供）：异基因造血干细胞移植（HSCT）是一种用于治疗晚期恶性血液病或其他血液疾病的治疗方法。HSCT涉及对患者进行化疗和/或放疗，然后移植来自同胞或无关匹配供体的造血干细胞。由于移植受者通过随后输注健康干细胞而从移植前预处理方案的骨髓抑制作用中被“拯救”，因此可以施用非常高剂量的化疗以努力克服恶性肿瘤显示的任何耐药性。此外，干细胞产品中存在的成熟供体细胞可以对可能仍然存在的任何残留癌症产生有效的免疫应答。然而，不幸的是，这些免疫反应并不特异于患病细胞，正常的宿主组织也会受损。这一过程被称为移植物抗宿主病（GVHD），可导致严重的皮疹、深度腹泻或肝损伤。GVHD通常用高剂量的类固醇治疗，这种疗法并不总是有效的，并且与大量的副作用有关。因此，实验室正在积极探索新的 治疗这种困难的疾病的方法。 最近，本提案的主要研究者Coghill博士发表了动物模型数据，显示缺乏淋巴结转运受体CC-趋化因子受体7（CCR 7）的供体细胞移植到受体小鼠时会产生大大减弱的GVHD反应。没有CCR 7的细胞不能正常运输到受体淋巴结，并且表现出在脾脏内扩增的能力降低。然而，重要的是，缺乏CCR 7的供体细胞能够在移植后产生有效的抗癌免疫作用，而供体调节性T细胞（一种抗炎细胞）能够在缺乏CCR 7的情况下预防GVHD。总的来说，这些发现表明，阻断CCR 7的功能可能被证明是一种新的有效方法，用于预防GVHD，而不会抑制有益的抗癌作用或干扰供体调节性T细胞下调过度攻击性免疫应答的能力。 目前没有可用于HSCT患者或动物模型研究的阻断CCR 7功能的药物。因此，该提议描述了开发针对CCR 7的拮抗剂的策略。对于这项工作，我们将使用基因工程细胞系，这些细胞系在CCR 7天然配体：CCL 19和CCL 21存在的情况下产生颜色信号。有了这些细胞，我们将自动筛选大约120，000个小分子的集合，以寻找具有CCR 7拮抗剂特性的药物，寻找能够在我们的主要报告基因检测中阻止颜色生成的化合物。然后评估来自初级筛选的活性物质的细胞毒性和针对CCR 7的特异性。接下来将通过评估先导化合物在体外损害趋化性（细胞运动）的能力来评估其功能，这是一个由CCR 7介导的过程。最终，将通过检查它们在小鼠移植模型中抑制GVHD的能力来评估有希望的化合物的体内功效。虽然超出了本提案的范围，但可以使用药物化学方法不断改进先导化合物，以最大限度地提高其对CCR 7的效力和选择性，并开发成用于接受干细胞移植的人类患者的药物。除了这种CCR 7拮抗剂发现的努力，机制研究，以更好地了解供体调节性T细胞如何在HSCT后没有CCR 7的功能，因为以前的研究表明，这种受体在其正常功能的关键作用。 该提案正在提交K 08指导职业发展奖。因此，该项目的目的是除了实现其具体的科学目标外，还为主要研究人员提供大量的教育内容。Coghill博士的长期目标是经营自己的实验室，重点研究GVHD发病机制和使用新型小分子治疗剂进行治疗和/或预防。虽然拥有强大的血液学和肿瘤学背景，这项工作将为Coghill博士提供一个机会，接受免疫学，细胞信号传导和药物发现早期阶段的额外深入指导。Coghill博士将从由Jonathan Serody博士和Stephen Frye博士领导的专家指导团队中学习第一手资料，他们分别是淋巴细胞贩运和药物开发领域的世界专家。还提出了一个正式的教学课程，包括药理学，细胞生物学，生物学和负责任的研究行为的课程。通过这些经验，Coghill博士将获得过渡到 一位独立的，由国家卫生研究院资助的实验室研究员。 公共卫生关系：异基因造血干细胞移植是一种用于治疗晚期血液相关癌症或其他血液疾病的治疗方式。然而，其有效性受到移植物抗宿主病（GVHD）的极大限制，GVHD是供体免疫细胞攻击正常受体组织的过程。该提案详细介绍了针对淋巴结归巢受体CC-趋化因子受体7（CCR 7）的候选药物的早期开发阶段，该药物最终可能用于预防人类干细胞移植患者的GVHD。