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Nanotechnology Targeting Novel CD154:CD11b Interactions for Transplant Tolerance

纳米技术靶向新型 CD154:CD11b 相互作用以提高移植耐受性

基本信息

批准号：
10622211
负责人：
Mandy L Ford
金额：
$ 106.46万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2023-04-20 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622211
关键词：
Acceleration Allogenic Allografting Alternative Therapies American Anti-CD40 Architecture Attenuated Binding Biological Biomedical Engineering CD8-Positive T-Lymphocytes Cancer Center Cells Clinic Clinical Research Clinical Trials Communication Data Event FOXP3 gene Frequencies Generations ITGAM gene ITGB2 gene Immune Immunosuppression Inferior Infiltration Integrins Journals Kidney Transplantation Ligands Lilium Macrophage Macrophage-1 Antigen Methods Modeling Monoclonal Antibodies Mus Myelogenous Nanotechnology Nature Outcome Paper Pathway interactions Peptides Production Publishing Reagent Regulatory T-Lymphocyte Reporting Residual state Role Signal Transduction Specificity T cell infiltration T cell response T-Lymphocyte TNFRSF5 gene TNFSF5 gene Techniques Testing Therapeutic Thrombophilia Transfusion Translating Transplant Recipients Transplantation Transplantation Tolerance allograft rejection antagonist clinical development clinical translation cytokine early phase clinical trial experimental study immune cell infiltrate immunoregulation in vivo inhibitor innovation isoimmunity monocyte mouse model nanoparticle nanotherapeutic nonhuman primate novel peptidomimetics preclinical study prevent receptor synergism therapeutic nanoparticles therapeutic target transcriptome transcriptomics transplant model

项目摘要

Abstract/ Summary Blockade of CD40-CD154 interactions is known to be a highly effective means of inhibiting alloreactive T cell responses and under some conditions inducing transplantation tolerance in both murine and non-human primate models. However, the potential of this therapeutic strategy to have a transformative impact on transplantation outcomes has yet to be realized. CD154 blockers were associated with adverse hypercoagulability in early clinical trials, instigating the therapeutic targeting of CD40 as an alternative therapy. However, CD40 blockers have failed in recent clinical trials due to insufficient efficacy. We therefore sought to determine if there is a biological explanation underlying the observed inferiority of blocking CD40 as compared to blocking CD154, in order to then devise ways to overcome it. In a 2020 study, we reported that CD11b is a second receptor for CD154 during alloimmunity, signaling through which is blocked by anti-CD154 reagents but not anti-CD40 reagents. We showed that CD154:CD11b interactions function locally within the allograft to enhance donor-reactive CD8+ T cell infiltration and accelerate allograft rejection. In addition, new preliminary data show that CD154 but not CD40 blockade results in the generation of graft-specific Foxp3+ iTreg, suggesting that the addition of CD154:CD11b blockade may boost iTreg generation in the context of anti-CD40. In this proposal, we will translate these findings into an NHP allogeneic renal transplant model to elucidate the role of CD154:CD11b blockade in transplantation tolerance, and to test a novel nanotherapeutic strategy to better target CD154:CD11b interactions and synergize with anti-CD40 in promoting transplantation tolerance in vivo. In the first Aim, we will elucidate the mechanisms by which CD154:CD11b blockade contributes to the inhibition of alloimmunity and the induction of Foxp3+ Treg, using novel techniques to identify and track alloreactive effector and regulatory T cells in NHP, and will use MIBI-TOF and transcriptomic approaches to interrogate the effects of blocking CD154:CD11b interactions on the immune architecture and transcriptomic profile of T cells, DC, and macrophage/monocytes within allografts. In the second Aim, we have developed a novel nanoparticle that is coated with a specific peptide inhibitor that prevents CD154:CD11b binding. Utilizing cutting edge nanotechnology to block this interaction, instead of a monoclonal antibody, offers the distinct advantage of the ability to bioengineer the nanoparticle with a separate immunomodulatory “payload” to further promote tolerance. Given the demonstrated ability of CD154 blockade to induce long-term, durable tolerance in NHP, our overall hypothesis is that combining the novel CD154:CD11b blocking nanoparticle with anti-CD40 will result in the establishment of transplantation tolerance.

摘要/总结已知阻断 CD40-CD154 相互作用是抑制同种反应性 T 细胞的高效方法反应并在某些条件下诱导小鼠和非人类的移植耐受灵长类动物模型。然而，这种治疗策略具有变革性影响的潜力移植结果尚未实现。 CD154 阻滞剂与不良反应相关早期临床试验中出现高凝状态，促使将 CD40 作为替代疗法。然而，CD40阻滞剂因疗效不足而在最近的临床试验中失败。因此我们力求确定观察到的相比之下阻断 CD40 的劣势是否存在生物学解释阻断CD154，以便随后想出克服它的方法。在 2020 年的一项研究中，我们报道 CD11b 是同种免疫过程中 CD154 的第二种受体，其信号传导被抗 CD154 阻断试剂，但不是抗 CD40 试剂。我们表明 CD154:CD11b 相互作用在同种异体移植物可增强供体反应性 CD8+ T 细胞浸润并加速同种异体移植物排斥。此外，新初步数据表明，CD154而非CD40阻断导致移植物特异性Foxp3+的产生 iTreg，表明添加 CD154:CD11b 阻断可能会促进 iTreg 的生成抗CD40。在本提案中，我们将把这些发现转化为 NHP 同种异体肾移植模型阐明 CD154:CD11b 阻断在移植耐受中的作用，并测试一种新型纳米治疗药物更好地靶向 CD154:CD11b 相互作用并与抗 CD40 协同促进移植的策略体内耐受性。在第一个目标中，我们将阐明 CD154:CD11b 阻断的机制有助于抑制同种免疫和诱导 Foxp3+ Treg，使用新技术来识别并追踪 NHP 中的同种异体反应性效应细胞和调节性 T 细胞，并将使用 MIBI-TOF 和转录组学探究阻断 CD154:CD11b 相互作用对免疫结构的影响的方法和同种异体移植物内 T 细胞、DC 和巨噬细胞/单核细胞的转录组谱。在第二个目标中，我们有开发了一种新型纳米颗粒，该纳米颗粒涂有特定的肽抑制剂，可防止 CD154:CD11b 绑定。利用尖端纳米技术而不是单克隆抗体来阻止这种相互作用，可以提供使用单独的免疫调节剂对纳米颗粒进行生物工程改造的能力的独特优势 “有效载荷”进一步促进宽容。鉴于 CD154 阻断已被证明具有诱导长期、 NHP 的持久耐受性，我们的总体假设是结合新型 CD154:CD11b 阻断具有抗CD40的纳米颗粒将导致移植耐受的建立。