Establishing Mixed Hematopoietic Chimerism in a Canine Model

在犬模型中建立混合造血嵌合状态

• 批准号: 8240003
• 负责人: Rainer F. Storb
• 金额: $ 68.88万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-08 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240003
• 关键词: Abdomen; Acute leukemia; Address; Adverse effects; Affect; Agonist; Allogenic; Allografting; Antigens; Astatine; Bone Marrow Purging; CD27 Antigens; CD28 gene; Canis familiaris; Cell Transplantation; Cells; Cervical; Characteristics; Chest; Chimera organism; Chimerism; Clinic; Clinical; Clinical Trials; Collaborations; Cyclophosphamide; Cyclosporine; Disease; Dose; Engraftment; Future; Genomics; Goals; HLA Antigens; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Home environment; Human; Immune; Immunosuppression; Immunosuppressive Agents; Knowledge; Label; Laboratories; Lymphocyte; Malignant - descriptor; Marrow; Minor; Modeling; Monoclonal Antibodies; Non-Malignant; Organ; Patients; Radiation Toxicity; Reaction; Regimen; Regulatory Pathway; Residual state; Risk; Role; Safety; Stem cells; T-Lymphocyte; Toxic effect; Translating; Transplant Recipients; Transplantation; Whole-Body Irradiation; base; conditioning; cytotoxic; efficacy testing; graft vs host disease; indium arsenide; irradiation; lymph nodes; mycophenolate mofetil; pre-clinical; preclinical study; success; tumor; Abdomen; Acute leukemia; Address; Adverse effects; Affect; Agonist; Allogenic; Allografting; Antigens; Astatine; Bone Marrow Purging; CD27 Antigens; CD28 gene; Canis familiaris; Cell Transplantation; Cells; Cervical; Characteristics; Chest; Chimera organism; Chimerism; Clinic; Clinical; Clinical Trials; Collaborations; Cyclophosphamide; Cyclosporine; Disease; Dose; Engraftment; Future; Genomics; Goals; HLA Antigens; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Home environment; Human; Immune; Immunosuppression; Immunosuppressive Agents; Knowledge; Label; Laboratories; Lymphocyte; Malignant - descriptor; Marrow; Minor; Modeling; Monoclonal Antibodies; Non-Malignant; Organ; Patients; Radiation Toxicity; Reaction; Regimen; Regulatory Pathway; Residual state; Risk; Role; Safety; Stem cells; T-Lymphocyte; Toxic effect; Translating; Transplant Recipients; Transplantation; Whole-Body Irradiation; base; conditioning; cytotoxic; efficacy testing; graft vs host disease; indium arsenide; irradiation; lymph nodes; mycophenolate mofetil; pre-clinical; preclinical study; success; tumor

PROJECT 1: ESTABLISHING STABLE MIXED HEMATOPOIETIC CHIMERISM INA CANINE MODEL We have established stable dog leukocyte antigen (DLA)-identical marrow grafts using sublethal conditioning with 2 Gy total body irradiation (TBI) before and a short course of immunosuppression with mycophenolate mofetil and cyclosporine after transplantation. The approach has been translated successfully into the clinic to treat patients with malignant (see Projects 3 and 4) and nonmalignant blood disorders. Project 1 will use the canine model to address three major issues of clinical allogeneic hematopoietic cell transplantation (HCT), avoiding long-term sequelae from conditioning regimens, controlling graft-vs.-host disease (GVHD) without need for and side effects from extended postgrafting immunosuppression, and enhancing graft-vs.- tumor effects without increasing the risk of GVHD. As for the first goal, we have both preclinical and clinical evidence that cytotoxic conditioning is not mandatory for allogeneic grafts to home. We will extend these observations and determine whether specific and non-toxic pretransplant tolerance induction, exploring six canine-specific blockers of T-cell co-stimulation and two agents affecting regulatory pathways, developed in our laboratory, can be substituted for the broad immunosuppression imparted by TBI and, this way, avoid short- and long-term radiation toxicities. As for the second goal, we will assess three alternative postgrafting manipulations for better control of both GVHD and HVG reactions which, if successful, would avert the need for extended postgrafting immunosuppression. To that end, we will study the immunosuppressive agent cyclophosphamide administered 3 days after marrow grafting, an astatine-211 (211At)-labeled monoclonal antibody against the T-cell activation antigen CD70, and an antagonist to the T-cell costimulatory blocker CD28 combined with an agonist to the down-regulatory molecule CTLA-4. The studies proposed under the first two goals are likely to generate stable mixed donor/host hematopoietic chimeras. Persistent host hematopoiesis can serve as model of persistent hematologic malignancy after HCT, a frequent problem encountered in patients transplanted under Projects 3 and 4. In collaboration with Project 2, we intend to identify minor non-DLA antigen disparities specific for hematopoietic cells (hematopoietic antigens) in given donor/recipient pairs using genomics approaches. This knowledge will provide the basis for future studies addressing the third goal in which donor lymphocytes rendered immune to host hematopoietic antigens will be infused in order to shift mixed to all-donor chimerism with no or minimal GVHD. If successful, we will test the efficacy of this approach in a canine model of experimentally induced acute leukemia. Results of these preclinical studies will be relevant for future clinical trials under Projects 3 and 4 and are likely to increase success and safety of allogeneic HCT in human patients.

项目1：建立稳定的混合造血嵌合体INA犬模型 我们已经建立了稳定的狗白细胞抗原（DLA） - 使用余生条件 在2 Gy全身照射（TBI）之前，与霉酚酸酯进行短暂的免疫抑制作用 移植后的莫夫蒂尔和环孢菌素。该方法已成功地转化为诊所 治疗恶性患者（请参见项目3和4）和非恶性血液疾病。项目1将使用 犬模型解决了临床同种异体造血细胞移植的三个主要问题 （HCT），避免了调节方案的长期后遗症，控制了移植物，宿主病（GVHD） 不需要扩展后的免疫抑制后副作用，并增强了移植物vs。 肿瘤的影响而不会增加GVHD的风险。至于第一个目标，我们具有临床前和临床 同种异体移植物在家中不是必需的细胞毒性调节的证据。我们将扩展这些 观察并确定特定和无毒的前植物耐受性诱导是否探索六个 T细胞共刺激的犬类特异性阻滞剂和两种影响调节途径的药物，在 我们的实验室可以代替TBI赋予的广泛免疫抑制 短期和长期辐射毒性。至于第二个目标，我们将评估三个替代后绑带 操纵更好地控制GVHD和HVG反应的操作，如果成功，这些反应将避免需求 用于扩展的后修建后免疫抑制。为此，我们将研究免疫抑制剂 骨髓嫁接后3天给药的环磷酰胺，Astatine-211（211AT）标记的单克隆 针对T细胞激活抗原CD70的抗体，以及对T细胞cotimulation阻滞剂的拮抗剂 CD28结合了下调节分子CTLA-4的激动剂。这些研究提出了 前两个进球可能会产生稳定的混合供体/宿主造血嵌合体。持续的主机 造血可以用作HCT后持续性血液学恶性肿瘤的模型，这是一个常见问题 在项目3和4下移植的患者中遇到。与项目2合作，我们打算 鉴定针对给定的造血细胞（造血抗原）特异的次要非DLA抗原差异 使用基因组学方法对供体/受体对。这些知识将为以后的研究提供基础 解决供体淋巴细胞对宿主造血抗原免疫的第三个目标 被注入以使其混合到无或最小GVHD的全钟嵌合。如果成功，我们将测试 这种方法在实验诱导的急性白血病的犬模型中的功效。这些结果 临床前研究将与项目3和4下的未来临床试验有关，并可能增加 同种异体HCT在人类患者中的成功和安全。