Novel Biologic Therapies for BMT: Mechanistic Evaluation in Rhesus Macaques

BMT 的新型生物疗法：恒河猴的机制评估

• 批准号: 8426132
• 负责人: Leslie S Kean
• 金额: $ 75.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426132
• 关键词: Acute Graft Versus Host Disease; Address; Adhesions; Adoptive Immunotherapy; Adult; Antibodies; Aplastic Anemia; Biological Markers; Biological Models; Biological Response Modifier Therapy; Bone Marrow; Bone Marrow Transplantation; CD28 gene; CD58 gene; Canis familiaris; Cell Adhesion; Cessation of life; Childhood; Clinic; Clinical; Clinical Trials; Diagnosis; Disease; Donor person; Evaluation; Face; Genetic; Graft Rejection; Hematological Disease; Human; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunophenotyping; Immunosuppression; Immunosuppressive Agents; Inborn Errors of Metabolism; Intervention; Investigation; Lead; Life; Macaca mulatta; Malignant - descriptor; Minority; Modeling; Mus; Non-Malignant; Organ Transplantation; Outcome; Pathway interactions; Patients; Phenotype; Plague; Population; Pre-Clinical Model; Preclinical Testing; Prevention; Primates; Prophylactic treatment; Public Health; Regimen; Registries; Regulatory T-Lymphocyte; Research Proposals; Risk; Serum; Siblings; Sickle Cell Anemia; Solid; Source; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic; Time; Transplant Recipients; Transplantation; Treatment Protocols; base; clinical application; disorder prevention; immune activation; insight; intercellular cell adhesion molecule; leukemia; novel; novel therapeutic intervention; novel therapeutics; prevent; public health relevance; research study

DESCRIPTION (provided by applicant): Bone marrow transplantation (BMT) represents the best chance for cure for a large number of malignant and non-malignant hematologic diseases. However, BMT implementation is currently limited by the many critical complications that accompany this potentially life-saving therapy. This is especially true for the majority of patients (70-80%) who lack MHC-matched sibling donors, and thus face risky, unrelated and/or MHC-mismatched 'alternative-donor' transplants (AD-BMT). Three major complications have plagued the implementation of AD-BMT. They are: (1) The increased risk of graft rejection. (2) The high rate of acute graft-versus-host-disease (aGvHD) that occurs in the setting of MHC-mismatched BMT; and (3) the profound immunosuppression that patients face after transplant, which renders them highly susceptible to infectious and malignant death in the immediate and long-term post-transplant periods. Prevention and treatment of these three complications represents the major unmet clinical need in BMT. One of the most significant barriers to progress in addressing these complications has been the lack of a preclinical model through which novel biologic therapeutic strategies, developed for human use, can be thoroughly and mechanistically investigated prior to clinical trials. Thus, due to the fact that (1) most novel therapies for BMT (including T cell costimulation blockade, T cell adhesion blockade and adoptive immunotherapy with regulatory T cells) cannot be accurately tested in either murine or canine models for aGvHD and (2) there has been no other translational BMT model available to test these biologics prior to clinical use, they have remained under-analyzed and under-utilized in clinical BMT, despite their burgeoning use in other disease states. In order to address the unmet need for their detailed, translational and mechanistic investigation we have developed a novel primate model of AD-BMT, capable both of dissecting mechanism as well as providing the critical translational bridge to clinical application of novel therapies. In this proposal, we describe experiments using the primate model which will determine both mechanism and efficacy of T cell costimulation blockade, T cell adhesion blockade, and regulatory T cell adoptive immunotherapy on the outcome of AD-BMT.

描述（由申请人提供）：骨髓移植（BMT）代表了治愈大量恶性和非恶性血液病的最佳机会。然而，BMT的实施目前受到许多严重并发症的限制，这些并发症伴随着这种可能挽救生命的治疗。这对于大多数缺乏MHC匹配的同胞供体的患者（70-80%）尤其如此，因此面临风险的、无关的和/或MHC不匹配的“替代供体”移植（AD-BMT）。三大并发症一直困扰着AD-BMT的实施。它们是：（1）增加移植物排斥反应的风险。(2)急性移植物抗宿主病（aGvHD）的发生率高，在设置的MHC不匹配的BMT;和（3）严重的免疫抑制，患者移植后面临的，这使得他们非常容易感染和恶性死亡，在立即和长期的移植后时期。这三种并发症的预防和治疗代表了BMT中未满足的主要临床需求。在解决这些并发症方面取得进展的最重要障碍之一是缺乏临床前模型，通过该模型，可以在临床试验之前彻底和机械地研究为人类使用而开发的新型生物治疗策略。因此，由于以下事实：（1）大多数用于BMT的新疗法（包括T细胞共刺激阻断、T细胞粘附阻断和用调节性T细胞的过继免疫疗法）不能在aGvHD的鼠或犬模型中准确地测试，并且（2）在临床使用之前没有其他可用于测试这些生物制剂的转化BMT模型，尽管它们在其他疾病状态中的应用日益广泛，但它们在临床BMT中的分析和利用仍然不足。为了解决未满足的需求，他们的详细，翻译和机制的调查，我们已经开发了一种新的灵长类动物模型的AD-BMT，既能够解剖机制，以及提供关键的翻译桥梁，以临床应用的新疗法。在这个建议中，我们描述了实验，使用灵长类动物模型，这将确定机制和疗效的T细胞共刺激阻断，T细胞粘附阻断，调节性T细胞过继免疫治疗的AD-BMT的结果。