Novel Biologic Therapies for BMT: Mechanistic Evaluation in Rhesus Macaques

描述（由申请人提供）：骨髓移植（BMT）是治疗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疗法。对于大多数缺乏mhc匹配的兄弟姐妹供体的患者（70-80%）来说尤其如此，因此面临风险，不相关和/或mhc不匹配的“替代供体”移植（AD-BMT）。三种主要并发症一直困扰着AD-BMT的实施。它们是：(1)移植排斥的风险增加。(2)急性移植物抗宿主病（aGvHD）在mhc不匹配的BMT中发生率高；(3)患者在移植后面临严重的免疫抑制，这使得他们在移植后的即时和长期内极易发生感染和恶性死亡。预防和治疗这三种并发症是BMT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开发的新型生物治疗策略。因此，由于(1)大多数治疗BMT的新疗法（包括T细胞共刺激阻断、T细胞粘附阻断和调节性T细胞过继免疫疗法）不能在aGvHD的小鼠或犬模型中进行准确的测试，(2)在临床使用之前没有其他可用于测试这些生物制剂的翻译BMT模型，尽管它们在其他疾病状态中的应用迅速发展，但它们在临床BMT中的分析和利用仍然不足。为了解决对AD-BMT的详细、转化和机制研究的未满足需求，我们开发了一种新的灵长类动物AD-BMT模型，既能解剖机制，又能为新疗法的临床应用提供关键的转化桥梁。在本文中，我们描述了使用灵长类动物模型的实验，该实验将确定T细胞共刺激阻断、T细胞粘附阻断和调节性T细胞过继免疫治疗对AD-BMT结果的机制和功效。

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.