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.

概括 建立可靠的方法来实现同种异体移植耐受性仍然是器官移植的最终目标。 我们以前报道了长期免疫抑制（i.s。） - 在 仅通过供体骨髓移植诱导瞬时造血嵌合。扩展 我们的方法的应用，现在必须提高造血的一致性和鲁棒性。 嵌合和同种异体耐受性； 2）通过识别可以诱导的新型药物来完善调节方案 混合嵌合不具有遗传毒性不良反应； 3）扩大对机制的理解 通过触发瞬态混合嵌合体的诱导，无I. S.肾脏同种异体移植接受。 有足够的证据表明，在移植期间的促炎反应会对长期产生不利影响 同种异体移植和耐受性诱导的术语结果。整合素CD11b/CD18（CD11b）在上面高度表达 先天免疫细胞的表面并调节先天免疫细胞中的几种关键促炎功能。 我们先前的研究表明，用MAB107（CD11b的第一类纯拮抗剂）阻止CD11b， 在长时间的本地肾脏或肾脏同种异体移植物长期温暖的缺血后，重新灌注损伤明显限制 非人类灵长类动物。这些观察结果导致了我们针对该应用的初步研究，该研究表明 MAB107接受者的肾脏同种异体移植物以及改善的造血嵌合体的长期结局。 因此，在AIM 1中，我们将测试以下假设：混合嵌合中用MAB107阻止CD11b 协议将引起更强大的同种异体移植耐受性。 为了减少调节方案对骨髓移植的合并症，我们最近表明 选择性Bcl-2抑制Venetoclax可显着促进造血嵌合体和同种异体移植耐受性 骨髓抑制并发症的最小。但是，完全消除了遗传毒性治疗 通过BCL-2抑制和最小无毒的总体照射，无法实现调理方案 （TBI）仍然需要。 Immtor是包裹雷帕霉素的合成可生物降解的纳米颗粒。可以 由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反应性 在NHP和人类中。因此，我们假设Immtor的有效免疫调节作用可能会更多 有效保护同种异体HSC免受同种免疫反应，使HSC植入没有任何响应 遗传毒性治疗。我们对IMMTOR的初步研究令人鼓舞，以多曲目混合嵌合为 被诱导而没有辐照和化学疗法。 最后，我们将阐明成功的I.S.无肾同种异体移植物生存 MAB107和IMMTOR诱导的瞬时造血嵌合体，利用广泛的体外和体内 具有新型免疫学方法的实验。我们的假设是主要的容忍机制将 被定义为调节性，但还涉及缺失机制。