Targeting innate immunity for induction of robust renal allograft tolerance

针对先天免疫诱导强大的肾同种异体移植耐受

• 批准号: 10622050
• 负责人: M. AMIN ARNAOUT
• 金额: $ 107.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-25 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622050
• 关键词: Adverse effects; Affect; Allogenic; Allograft Tolerance; Allografting; Anti-CD40; Antigens; B-Lymphocytes; BCL2 gene; Bone Marrow; Bone Marrow Transplantation; Cells; Chimerism; Clinical; Clinical Trials; Dendritic Cells; Dose; Dual-role transvestism; Encapsulated; Failure; Family suidae; Goals; HLA Antigens; Hematopoietic; Hematopoietic stem cells; Human; ITGAM gene; ITGB2 gene; Immune; Immunologic Receptors; Immunologics; Immunosuppression; In Vitro; Inferior; Inflammatory; Inflammatory Response; Injury to Kidney; Innate Immune Response; Integrin Inhibition; Integrins; Investigation; Ischemia; Kidney; Lead; Maintenance; Methods; Modality; Modeling; Monoclonal Antibodies; Mus; Myeloid Cells; Natural Immunity; Organ Transplantation; Outcome; Pathway interactions; Peripheral; Protocols documentation; Regimen; Reperfusion Injury; Reporting; Role; Sirolimus; Solid; Surface; TNFSF5 gene; Testing; Transplant Recipients; Transplantation; Transplantation Tolerance; Warm Ischemia; Whole-Body Irradiation; adaptive immune response; adaptive immunity; antagonist; chemotherapy; comorbidity; conditioning; exosome; experimental study; extracellular vesicles; genotoxicity; hematopoietic engraftment; immunoregulation; improved; in vivo; irradiation; kidney allograft; living kidney donor; mTOR Inhibitor; nanoparticle; nonhuman primate; novel; patient population; preclinical study; research study; response

SUMMARY Establishing a reliable method to achieve allograft tolerance remains an ultimate goal in organ transplantation. We previously reported long-term immunosuppression (I.S.)-free renal allograft survival in humans after induction of only transient hematopoietic chimerism through donor bone marrow transplantation. To expand the application of our approach, it is now imperative to 1) improve the consistency and robustness of hematopoietic chimerism and allograft tolerance; 2) refine the conditioning regimen by identifying novel agents that can induce mixed chimerism without genotoxic adverse effects; and 3) expand the understanding of mechanisms whereby I.S.-free renal allograft acceptance via induction of transient mixed chimerism is achieved. There is ample evidence that proinflammatory responses during the peri-transplant period adversely affects long- term outcome of the allograft and tolerance induction. Integrin CD11b/CD18 (CD11b) is highly expressed on the surface of innate immune cells and modulates several key proinflammatory functions in innate immune cells. Our previous studies showed that blocking CD11b with mAb107, a first-in-class pure antagonist of CD11b, markedly limits reperfusion injury after prolonged warm ischemia of native kidney or kidney allografts in nonhuman primates. These observations led to our preliminary studies for this application that revealed superior long-term outcome of renal allografts as well as improved hematopoietic chimerism in recipients of mAb107. Therefore, in Aim 1, we will test the hypothesis that blocking CD11b with mAb107 in our mixed chimerism protocol will induce a more robust allograft tolerance. To reduce comorbidity of our conditioning regimen for bone marrow transplantation, we recently showed that selective Bcl-2 inhibition with Venetoclax significantly promotes hematopoietic chimerism and allograft tolerance with minimal myelosuppressive complications. However, complete elimination of genotoxic treatments from the conditioning regimen was not achieved with Bcl-2 inhibition and a minimal non-toxic dose of total body irradiation (TBI) was still required. ImmTOR is synthetic biodegradable nanoparticles encapsulating rapamycin. It can be rapidly endocytosed by dendritic cells and other myeloid cells and induces antigen-specific non-responsiveness in NHPs and humans. We therefore hypothesize that potent immunomodulatory effects of ImmTOR may more effectively protect allogeneic HSCs from alloimmune responses, allowing engraftment of HSCs without any genotoxic treatments. Our preliminary studies with ImmTOR are encouraging with multilineage mixed chimerism being induced without irradiation and chemotherapy. Finally, we will elucidate the mechanistic pathways involved in successful I.S.-free renal allograft survival by transient hematopoietic chimerism induced by mAb107 and ImmTOR, utilizing extensive in vitro and in vivo experiments with novel immunological approaches. Our hypothesis is that the major tolerance mechanism will be defined as regulatory but deletional mechanisms are also involved.

总结 建立一种可靠的方法来实现同种异体移植耐受仍然是器官移植的最终目标。 我们以前报道过长期免疫抑制（I.S.）-移植肾存活率 通过供体骨髓移植仅诱导短暂造血嵌合体。扩大 应用我们的方法，现在必须1）提高造血的一致性和稳健性 嵌合体和同种异体移植物耐受; 2）通过鉴定可以诱导嵌合体和同种异体移植物耐受的新药物来改进预处理方案。 混合嵌合体，无遗传毒性不良反应; 3）扩大对机制的理解， I.S.-通过诱导短暂的混合嵌合体实现了游离肾同种异体移植物的接受。 有充分的证据表明，在移植前后的促炎反应对长期的免疫功能有不利影响。 同种异体移植物的长期结果和耐受诱导。整合素CD 11b/CD 18（CD 11b）在细胞表面高度表达 在先天性免疫细胞的表面，并调节先天性免疫细胞中的几个关键促炎功能。 我们以前的研究表明，用单克隆抗体107阻断CD 11b，单克隆抗体107是一种一流的CD 11b纯拮抗剂， 显著限制了自体肾或同种异体肾移植物长时间热缺血后的再灌注损伤， 非人类灵长类动物这些观察结果导致我们对该应用程序进行初步研究，发现其具有上级 肾同种异体移植的长期结果以及mAb 107接受者中改善的造血嵌合体。 因此，在目的1中，我们将检验在我们的混合嵌合体中用mAb 107阻断CD 11b 方案将诱导更稳健的同种异体移植物耐受性。 为了减少骨髓移植预处理方案的并发症，我们最近发现， 维奈托克选择性Bcl-2抑制剂显著促进造血嵌合体和同种异体移植耐受 骨髓抑制并发症很小然而，完全消除遗传毒性治疗， 预处理方案不能用Bcl-2抑制和最小无毒剂量的全身照射来实现 (TBI)仍然需要。ImmTOR是合成的可生物降解的纳米颗粒，包封雷帕霉素。可以 被树突状细胞和其他髓样细胞快速内吞并诱导抗原特异性非应答性 在NHP和人类中。因此，我们假设ImmTOR的强效免疫调节作用可能更多地 有效地保护同种异体HSC免受同种异体免疫应答，允许HSC的植入而没有任何 遗传毒性治疗。我们对ImmTOR的初步研究是令人鼓舞的多谱系混合嵌合体 不经放疗和化疗诱导。 最后，我们将阐明成功的I.S.-游离移植肾存活率 利用广泛的体外和体内研究， 新的免疫学方法的实验。我们的假设是，主要的耐受机制将 被定义为监管，但删除机制也参与其中。