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

基本信息

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
项目类别：
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

项目摘要

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.

概括建立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。我们之前报道过，人类肾移植术后长期无免疫抑制（I.S.）存活率通过供体骨髓移植仅诱导短暂的造血嵌合。为了扩大应用我们的方法，现在当务之急是1）提高造血的一致性和鲁棒性嵌合现象和同种异体移植物耐受性； 2）通过识别可诱导的新药物来完善预处理方案混合嵌合现象，无遗传毒性副作用； 3）扩大对机制的理解通过诱导短暂的混合嵌合状态实现了无 I.S. 的同种异体肾移植接受。有充分的证据表明，围移植期的促炎症反应会对长期健康产生不利影响。同种异体移植和耐受诱导的长期结果。整合素 CD11b/CD18 (CD11b) 在先天免疫细胞的表面并调节先天免疫细胞中的几个关键促炎功能。我们之前的研究表明，用 mAb107（一种一流的 CD11b 纯拮抗剂）阻断 CD11b，显着限制自体肾或同种异体肾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此应用进行了初步研究，结果显示出优越的性能同种异体肾移植的长期结果以及 mAb107 受体的造血嵌合状态得到改善。因此，在目标 1 中，我们将测试在我们的混合嵌合体中用 mAb107 阻断 CD11b 的假设方案将诱导更强大的同种异体移植耐受。为了减少骨髓移植预处理方案的合并症，我们最近表明： Venetoclax 选择性 Bcl-2 抑制显着促进造血嵌合和同种异体移植耐受骨髓抑制并发症最少。然而，彻底消除遗传毒性治疗通过 Bcl-2 抑制和最小无毒剂量的全身照射未能实现预处理方案（TBI）仍然是必需的。 ImmTOR 是封装雷帕霉素的合成可生物降解纳米颗粒。它可以是被树突状细胞和其他骨髓细胞快速内吞并诱导抗原特异性无反应在 NHP 和人类中。因此，我们假设 ImmTOR 的有效免疫调节作用可能更有效。有效保护同种异体 HSC 免受同种免疫反应，使 HSC 能够在没有任何免疫反应的情况下植入基因毒性治疗。我们对 ImmTOR 的初步研究令人鼓舞的是多谱系混合嵌合现象无需放疗和化疗即可诱导。最后，我们将通过以下方式阐明成功的无 I.S. 同种异体肾移植存活的机制途径： mAb107 和 ImmTOR 广泛利用体外和体内诱导的短暂造血嵌合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，但也涉及删除机制。