Bcl-2 and Mcl-1 inhibition for induction of hematopoietic chimerism and renal allograft tolerance without myelosuppression in nonhuman primates

在非人灵长类动物中抑制 Bcl-2 和 Mcl-1 可诱导造血嵌合和肾同种异体移植耐受，而无需骨髓抑制

• 批准号: 10634698
• 负责人: TATSUO KAWAI
• 金额: $ 92.27万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634698
• 关键词: Achievement; Address; Allograft Tolerance; Allografting; Antigens; Apoptosis; Apoptotic; BCL2 gene; Bone Marrow; Bone Marrow Transplantation; Cells; Chemotherapy and/or radiation; Chimerism; Clinical; Clinical Trials; Clonal Expansion; Clone Cells; Cryopreservation; Data; Disease; Dual-role transvestism; FDA approved; Family suidae; Future; Goals; Grant; HLA Antigens; Hematopoietic; Hematopoietic stem cells; Human; Immune; Immunologics; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Kidney; Kidney Transplantation; Leukopenia; Living Donors; MCL1 gene; Macrophage; Maintenance; Malignant Neoplasms; Metabolic Diseases; Methods; Modality; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myelosuppression; Neutropenia; Organ; Organ Transplantation; Outcome; Pathway interactions; Pharmaceutical Preparations; Process; Protocols documentation; Radiation; Regimen; Reporting; Reproducibility; Role; T-Lymphocyte; TNFSF5 gene; Testing; Therapeutic; Thrombocytopenia; Time; Transplant Recipients; Transplantation; chemotherapy; clinical application; conditioning; experimental study; extracellular vesicles; improved; in vivo; inhibitor; irradiation; kidney allograft; living kidney donor; monocyte; mortality; nonhuman primate; novel; novel strategies; post-transplant; preclinical study; research study; standard of care

SUMMARY Organ transplantation has become the standard of care for many end-state diseases, but currently requires life-long administration of potent immunosuppressive drugs. This results in increased morbidity and mortality from infection, malignancy and other metabolic disorders. Establishing a reliable method to achieve allograft survival without ongoing immunosuppression (I.S.) remains an important goal. We previously reported achievement of long-term I.S.-free renal allograft survival in humans after induction of only transient hematopoietic chimerism through donor bone marrow (BM) transplantation. To expand the application of our approach, it is imperative to improve the levels and consistency of hematopoietic chimerism without increasing myelosuppression associated with the current conditioning regimen. We have identified a novel strategy in nonhuman primates that addresses this obstacle by enhancing intrinsic apoptosis of selective hematopoietic cells using a B cell lymphoma-2 inhibitor (Bcl- 2i). This approach significantly improves chimerism levels and duration and achieves I.S.-free renal allograft survival without neutropenia and thrombocytopenia. These studies did reveal that costimulatory blockade (CB) remains essential for tolerance induction with Bcl-2i. Therefore, we will first define a protocol using only FDA approved (or in the process of being FDA approved) CB, including 1) anti-CD2 mAb, 2) Fc-modified anti-CD154 mAb, and 3) Belatacept. More recently, with the support of an exploratory R21 grant, we have found that induction of hematopoietic chimerism appears to be possible even without any chemo/radiation therapy, if hematopoietic stem cells are adequately depleted from BM niches with a Bcl-2i in combination with another proapoptotic agent that inhibits Myeloid cell leukemia 1 (Mcl-1). In our proposal, we will therefore further pursue the ultimate goal to induce hematopoietic chimerism without any radiation or chemotherapeutic drugs. Also of major importance for more widespread clinical applicability, we will extend the most successful Bcl-2i based protocol to our novel “delayed tolerance” approach. This will, for the first time, make tolerance induction strategies available to recipients of deceased donor allografts using cryopreserved BM, as well as to ongoing living donor transplant recipients whose kidney donor is available to provide hematopoietic stem cells. Finally, we will elucidate the mechanistic pathways involved in successful I.S.-free renal allograft survival by transient hematopoietic chimerism and proapoptotic agents, utilizing extensive in vitro and in vivo experiments with novel immunological approaches.

概括 器官移植已成为许多终态疾病的护理标准，但目前 需要终生服用强效免疫抑制药物，这会导致发病率增加。 以及感染、恶性肿瘤和其他代谢紊乱引起的死亡率。建立可靠的方法。 在不持续免疫抑制（I.S）的情况下实现同种异体移植存活仍然是一个重要目标。 我们之前报道过，人类同种异体肾移植物在 通过供体骨髓（BM）移植仅诱导短暂的造血嵌合。 为了扩大我们的方法的应用，必须提高方法的水平和一致性 造血嵌合状态，不会增加与当前调节相关的骨髓抑制 我们在非人类灵长类动物中发现了一种新策略，可以通过以下方式解决这一障碍。 使用 B 细胞淋巴瘤 2 抑制剂 (Bcl- 2i) 这种方法显着提高了嵌合水平和持续时间，并实现了无 I.S. 的肾。 这些研究确实揭示了没有中性粒细胞减少症和血小板减少症的同种异体移植物的存活率。 共刺激阻断 (CB) 对于 Bcl-2i 的耐受诱导仍然至关重要，因此，我们将。 首先仅使用 FDA 批准的（或正在 FDA 批准的过程中）CB 定义一个协议，包括 1) 抗 CD2 mAb，2) Fc 修饰的抗 CD154 mAb，以及 3) 最近获得了 Belatacept 的支持。 在一项探索性 R21 资助中，我们发现造血嵌合的诱导似乎是 如果造血干细胞未充分耗尽，即使没有任何化疗/放射治疗，也有可能 来自 BM 生态位，含有 Bcl-2i 和另一种抑制骨髓细胞的促凋亡剂 因此，在我们的建议中，我们将进一步追求诱发白血病1（Mcl-1）的最终目标。 造血嵌合无需任何放射或化疗药物。 对于更广泛的临床应用也具有重要意义，我们将扩展最成功的 基于 Bcl-2i 的协议将首次实现我们新颖的“延迟耐受”方法。 使用冷冻保存的已故供体同种异体移植物的受者可采用的耐受诱导策略 BM，以及正在进行的活体移植接受者，其肾脏捐赠者可以提供 造血干细胞。 最后，我们将阐明成功的无 I.S. 同种异体肾移植的机制途径 通过短暂的造血嵌合和促凋亡剂存活，在体外和体外广泛使用 采用新的免疫学方法进行体内实验。