Liver allograft tolerance induction by Bcl-2 inhibition and delayed donor bone marrow infusion

通过 Bcl-2 抑制和延迟供体骨髓输注诱导同种异体肝移植耐受

• 批准号: 10176407
• 负责人: Shoko Kimura
• 金额: $ 20.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176407
• 关键词: Achievement; Allogeneic Bone Marrow Transplantation; Allogenic; Allograft Tolerance; Allografting; Apoptosis; Apoptotic; BCL2 gene; Bone Marrow; Bone Marrow Transplantation; Cardiovascular Diseases; Cells; Chimerism; Chronic Kidney Failure; Clinical; Clinical Trials; Cyclophosphamide; Cyclosporine; Dose; FDA approved; Goals; Hematopoietic; Hematopoietic stem cells; Human; Immunosuppression; Immunosuppressive Agents; Infection; Infusion procedures; Kidney; Kidney Transplantation; Kinetics; Liver; Liver Failure; Liver diseases; Lymphoid Cell; Malignant Neoplasms; Messenger RNA; Metabolic Diseases; Modeling; Monkeys; Myeloid Cells; Myelosuppression; Myelosuppressive Therapy; Nature; Organ; Pathway interactions; Patients; Preparation; Primary carcinoma of the liver cells; Protocols documentation; Recurrence; Regimen; Regulatory T-Lymphocyte; Reporting; Research Proposals; Risk; Steroids; T-Lymphocyte; Testing; Thymus Gland; Time; Toxic effect; Translating; Transplant Recipients; Transplantation; Viral hepatitis; Virus Diseases; Whole-Body Irradiation; Withdrawal; clinical application; clinically relevant; conditioning; efficacy evaluation; improved; inhibitor/antagonist; irradiation; kidney allograft; liver allograft; liver transplantation; nonalcoholic steatohepatitis; nonhuman primate; novel strategies; post-transplant; pre-clinical; response; skin allograft; stem cell engraftment; transplant model

PROJECT SUMMARY / ABSTRACT Although the liver has long been considered a tolerogenic organ, most liver transplant recipients require lifelong immunosuppression, which can have negative consequences, such as recurrence of viral hepatitis or hepatocellular carcinoma. All transplant recipients, regardless of organ, have an increased risk of developing chronic kidney disease, infection, malignancies, or cardiovascular disease. Tolerance induction, therefore, would be a significant long-term benefit in terms of allograft and patient survival. We have successfully achieved renal allograft tolerance using a mixed chimerism approach in concert with a non-myeloablative regimen in both humans and non-human primates (NHPs). However, the clinical application of this approach in liver transplant recipients is not as practical or safe as in kidney transplant recipients because liver failure patients tend to be sicker at the time of transplantation and unable to withstand the toxicity of the conditioning regimen. However, if the bone marrow transplant is delayed and if we reduce the toxicity of the myelosuppressive conditioning regimen, these approaches can be safely applied. Cippa et al. recently reported a novel approach to hematopoietic stem cell (HSC) engraftment without myelosuppression using a B cell lymphoma-2 (Bcl-2) inhibitor. This novel approach has been successfully translated to an NHP kidney transplant model. Using an FDA-approved, highly selective Bcl-2 inhibitor, ABT-199 (venetoclax), with reduced dose (1.5 G) total body irradiation (TBI), we have been able to achieve significantly improved mixed chimerism and renal allograft tolerance in NHPs. Encouraged by these preliminary results, we hypothesize that mixed chimerism and liver allograft tolerance can be induced even more effectively without any myelosuppressive treatments. The primary objective of this proposal is to evaluate the efficacy of selective Bcl-2 inhibition to induce mixed chimerism for liver allograft tolerance in a clinically relevant NHP model. HLA mismatched cynomologus monkeys will be used as both donors and recipients for allogeneic orthotopic liver transplantation. All recipients will initially receive triple-drug immunosuppressive regimen (CyA, MMF, steroid) consistent with the peri-transplant period. Several months (2-3) after orthotopic liver transplant (OLTx), the recipients will undergo non-myeloablative conditioning (thymic irradiation, with or without ABT-199) and DBMT, followed by a short post-transplant course of Belatacept (20mg/kg on days 0, 2, 5 and 12) and one month course of CyA to see whether Bcl-2 inhibitor can induce mixed chimerism and liver allograft tolerance. We will then study the effect of Bcl-2 inhibition on alloreactive T lymphocytes and regulatory T cells to investigate the mechanism.

项目总结/摘要 虽然肝脏长期以来一直被认为是一个致耐受性器官，但大多数肝移植受者需要终身 免疫抑制，可能产生负面后果，如病毒性肝炎复发或 肝细胞癌所有移植受者，无论器官如何，都有增加的风险， 慢性肾病、感染、恶性肿瘤或心血管疾病。因此，耐受诱导， 在同种异体移植物和患者存活方面将是显著的长期益处。 我们已经成功地实现了肾移植耐受使用混合嵌合体的方法与音乐会， 在人类和非人类灵长类动物（NHP）中的非清髓性方案。然而，临床应用 这种方法在肝移植受者中并不像在肾移植受者中那样实用或安全， 肝衰竭患者在移植时往往病情更重， 调理方案。然而，如果骨髓移植被推迟，如果我们减少毒性的， 骨髓抑制预处理方案，这些方法可以安全地应用。Cippa等人最近报道， 使用B细胞的无骨髓抑制的造血干细胞（HSC）移植的新方法 淋巴瘤-2（Bcl-2）抑制剂。这种新的方法已成功地转化为NHP肾移植 模型 使用FDA批准的高选择性Bcl-2抑制剂ABT-199（venetoclax），总剂量减少（1.5 G） 全身照射（TBI），我们已经能够实现显着改善混合嵌合体和肾移植 NHP的耐受性。受这些初步结果的鼓舞，我们假设混合嵌合体和肝脏 甚至可以更有效地诱导同种异体移植物耐受而无需任何骨髓抑制治疗。主 本提案的目的是评估选择性Bcl-2抑制诱导混合嵌合体的功效， 临床相关NHP模型中的肝移植耐受。将使用HLA不匹配的食蟹猴 作为同种异体原位肝移植的供体和受体。所有收件人最初将收到 三联药物免疫抑制方案（CyA、MMF、类固醇）与移植围手术期一致。几 原位肝移植（OLTx）后2-3个月，受者将接受非清髓性预处理 （胸腺照射，有或没有ABT-199）和DBMT，随后是一个短期的移植后过程， Belatacept（20 mg/kg，第0、2、5和12天）和CyA一个月疗程，观察Bcl-2抑制剂是否能 诱导混合嵌合体和肝移植耐受。然后，我们将研究Bcl-2抑制对 同种异体反应性T淋巴细胞和调节性T细胞，以探讨其机制。