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; 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最终状态疾病的护理标准，但目前 需要终身给予有效的免疫抑制药物。这导致发病率增加 以及感染，恶性肿瘤和其他代谢障碍的死亡率。建立可靠的方法 在不进行免疫抑制（I.S.）的情况下达到同种异体移植生存仍然是一个重要目标。 我们以前报道了长期无i.S。无肾同种异体移植物的生存 仅通过供体骨髓（BM）移植诱导瞬时造血嵌合体。 为了扩大我们的方法的应用，必须提高 造血嵌合体不增加与当前条件相关的骨髓抑制 方案。我们已经确定了非人类隐私的新型策略，该策略通过 使用B细胞淋巴瘤-2抑制剂（BCL-- 2i）。这种方法可显着提高嵌合的水平，持续时间，并实现无肾脏 无中性粒细胞减少和血小板减少症的同种异体移植生存。这些研究确实表明 contimulation封锁（CB）对于用BCL-2I耐受性诱导仍然至关重要。因此，我们会的 首先仅使用FDA批准（或在被FDA批准的过程中）定义协议，包括 1）抗CD2 mAb，2）FC修饰的抗CD154 mAb和3）Belatacept。最近，在支持下 在探索性R21赠款中，我们发现造血嵌合体的诱导似乎是 即使没有任何化学/放射疗法，也可能存在造血干细胞充分耗尽 来自BM-2I的BM壁ni与另一种抑制髓样细胞的促凋亡剂的结合 白血病1（MCL-1）。因此，在我们的提案中，我们将进一步追求最终目标 没有任何放射线或化学治疗药物的造血嵌合体。 对于更广泛的临床适用性，我们也将扩展最成功的最重要的 基于BCL-2I的规程，我们的新颖的“延迟耐受性”方法。这将首次做 使用冷冻保存的已故供体合金的接收者可用的耐受性诱导策略 BM，以及正在进行的活捐赠者移植者，他们的肾脏供体可以提供 造血干细胞。 最后，我们将阐明成功I.S.无肾脏透视仪中涉及的机械途径 使用广泛的体外和 具有新型免疫学方法的体内实验。