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: 8449704
• 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/8449704
• 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; Instruction; K-Series Research Career Programs; Knock-out; Laboratories; Lead; Learning; Ligands; 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; liver injury; 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.

描述（由申请人提供）：同种异体造血干细胞移植（HSCT）是一种治疗方法，用于治疗晚期血液学恶性肿瘤或其他血液疾病。 HSCT涉及对患者进行化学疗法和/或放射线的给药，然后是兄弟姐妹或不相关匹配供体的造血干细胞的移植。由于移植受者是从骨髓抑制移植前调节方案的抑制作用中“救出的”，因此可以通过随后的健康干细胞输注，因此可以进行非常高剂量的化疗，以克服恶性肿瘤表现出的任何耐药性。此外，存在于干细胞产物中的成熟供体细胞可以对可能存在的任何残留癌症进行有效的免疫反应。但是，不幸的是，这些免疫反应并非针对患病细胞的特异性，正常宿主组织也可能受损。该过程被称为移植物抗宿主病（GVHD），可能导致严重的皮疹，严重的腹泻或肝损伤。 GVHD最常接受高剂量的类固醇治疗，这种疗法并不总是有效且与实质性副作用相关的疗法。结果，实验室正在积极探索新的 治疗这种困难疾病的方法。 最近，本提案的主要研究人员Coghill博士发表了动物模型数据，表明缺乏淋巴结流量运输受体CC-Semokine受体7（CCR7）的供体细胞会产生大大减弱的GVHD反应，而当移植到受体中。没有CCR7的细胞未能正常流动到受体淋巴结，并显示出脾内扩展的能力降低。然而，重要的是，缺乏CCR7的供体细胞能够在移植后安装有效的抗癌免疫效应，并且在没有CCR7的情况下，供体调节T细胞（抗炎细胞群）能够防止GVHD。总的来说，这些发现表明，阻止CCR7的功能可能被证明是一种新的有效方法，可以防止GVHD而不抑制有益的抗癌作用或干扰供体调节性T细胞下调过度侵略性免疫反应的能力。 目前，没有阻止CCR7功能的药物可用于HSCT患者或用于动物模型中的研究。结果，该提案描述了一种针对CCR7的拮抗剂的策略。对于这项工作，我们将使用基因工程的细胞系，在CCR7：CCL19和CCL21的天然配体存在下产生颜色信号。使用这些细胞，我们将用于机器人筛选具有CCR7拮抗剂特性的大约120,000个小分子的集合，寻找能够在我们的主要报告基因测定中阻止颜色产生的化合物。然后，将对主要筛查的活性物进行细胞毒性和针对CCR7的特异性进行评估。接下来，将通过评估其在体外损害趋化性（细胞运动）的能力来评估铅化合物的功能，这一过程由CCR7介导。最终，通过检查其在小鼠移植模型中抑制GVHD的能力，可以评估有希望的化合物在体内的疗效。虽然除本提案的范围之外，但可以使用药物化学方法来不断地完善铅化合物，从而最大程度地提高其对CCR7的效力和选择性，并将其发展为用于干细胞移植的人类患者的药物。除了这种CCR7拮抗剂发现工作外，还描述了机械研究，以更好地了解供体调节性T细胞在没有CCR7的HSCT后如何起作用，因为先前的研究表明该受体在其正常功能中起着至关重要的作用。 该提案正在提交K08指导的职业发展奖。结果，该项目旨在为主要研究者提供实质性的教育组成部分，此外还实现了其特定的科学目标。 Coghill博士的长期TRM目标是运营自己的实验室，重点是GVHD发病机理以及新型小分子疗法的治疗和/或预防。这项工作在血液学和肿瘤学方面具有强大的背景，但Coghill博士将有机会获得免疫学，细胞信号传导和药物发现早期阶段的额外深入指导。 Coghill博士将向由Drs领导的专家指导团队进行直接学习。乔纳森·塞迪（Jonathan Serody）和斯蒂芬·弗莱（Stephen Frye），分别是淋巴细胞贩运和药物开发领域的世界专家。还提出了一个形式化的教学课程，包括药理学，细胞生物学，助学金和负责任的研究课程。通过这些经验，Coghill博士将获得过渡到过渡到的技能 独立的NIH资助实验室研究员。