Lymph nodes at the crossroads of allo immunity and regulation

淋巴结处于同种异体免疫和调节的十字路口

• 批准号: 10662304
• 负责人: Reza Abdi
• 金额: $ 126.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-27 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662304
• 关键词: Alloantigen; Anti-Inflammatory Agents; Area; Biology; Cicatrix; Cues; Data; Development; Dimensions; Disease; Equilibrium; Fostering; Generations; Goals; Graft Rejection; Immune; Immune Tolerance; Immune response; Immunity; Immunosuppression; Immunotherapy; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Laminin; Light; Mediating; Microanatomy; Modeling; Molecular; Monoclonal Antibodies; Myofibroblast; Nanodelivery; Nature; Organ; Organ Transplantation; Outcome; Pathway interactions; Patients; Play; Procedures; Reaction; Regulation; Regulatory T-Lymphocyte; Research Personnel; Resources; Rest; Reticular Cell; Role; Scientist; Site; Solid; Stromal Cells; Structure; Subcellular Anatomy; T memory cell; T-Lymphocyte; TNFSF5 gene; Technology; Testing; Therapeutic; Transplantation; Transplantation Tolerance; allograft rejection; cell transformation; clinical application; combinatorial; fiber cell; high voltage electron microscopy; immune activation; immunoregulation; improved; improved outcome; inflammatory milieu; inhibitor; innovation; isoimmunity; lymph node microenvironment; lymph nodes; member; nanoparticle; novel; programs; response; restoration; senescence; skills; synergism; targeted delivery; targeted treatment; translational applications

OVERALL – SUMMARY/ABSTRACT Organ transplantation remains a mainstay therapeutic strategy for patients with end organ diseases. One of the highest unmet needs to improve long-term transplant outcomes is devising more effective immune modulation. This requires innovative mechanistic studies of transplant alloimmunity. The lymph node (LN) is the quintessential organ of alloimmunity. While the recognition of alloantigens in the LN is fundamental to the generation of alloreactive T cells, our groups also have shown that the LN plays an important role in alloimmune-regulation and Treg-mediated tolerance. These multifaceted functions rest on the nature of LNs as extremely specialized organs with unique microvasculature, stromal fibers, and stromal cells (referred to as fibroblastic reticular cells [FRCs]). Our overarching hypothesis is that manipulating the microenvironment of LNs will provide a unique opportunity to direct the alloimmune reaction towards an anti-inflammatory tolerance response. Our major goals are to understand the cellular and molecular mechanisms that govern the microanatomical adaptation of the LN during immune activation or tolerance induction, and to develop highly innovative therapeutic strategies that promote a regulatory LN microenvironment and result in immune tolerance. This PPG sets forth a platform for connecting two teams (Drs. Abdi and Bromberg) with complementary skills and expertise in LN alloimmune-biology. Project 1 will test the hypothesis that sustained activation of FRCs of the LN during alloimmunity will result in FRC transformation to proinflammatory myofibroblasts creating an inflammatory milieu within the LN, which would further promote alloimmunity. Our corollary hypothesis is that restoration of the function of FRCs and microanatomy of the LNs will enhance their immunoregulatory function and promote tolerance. Aim 1 will examine the role of the HVEM/LIGHT pathway in the differentiation of FRCs into proinflammatory myofibroblasts, thereby creating an inflammatory milieu within the LN microenvironment and promoting transplant immunity. Aim 2 will investigate the mechanisms by which fibrotic FRCs promote a pro-inflammatory response in the LN. Aim 3 will reprogram the stroma of LNs via FRC delivery or LN-targeted delivery of senescence inhibitors to further promote alloimmune tolerance. Project 2 will test the hypothesis that FRCs regulate the LN laminin α4:α5 (LAMA4/LAMA5) ratio and control the fate of the immune response. Aim 1 will define the role of stromal cells in controlling the balance of LAMA4 and LAMA5. Aim 2 will define the role of LTβR as a key pathway in regulating the formation of LAMA5. Aim 3 will use targeted delivery of anti-CD40L and anti-LAMA5 mAbs to the LN to promote tolerance. An Administrative Core (Core A) and Nanoparticle and FRC Core (Core B) will provide the infrastructure and resources to support these two projects. The ultimate goal of these well-integrated and highly synergistic Projects and Cores is to generate transformative mechanistic data, which will lay the groundwork for developing highly targeted and innovative therapeutic strategies for transplantation.

总体--摘要/摘要 器官移植仍然是终末期器官疾病患者的主要治疗策略。其中之一 改善长期移植结果的最高未满足需求是设计更有效的免疫 调制。这就需要对移植同种免疫进行创新的机制研究。淋巴结(LN)是 同种异体免疫的典型器官。而对LN中同种异体抗原的识别是 同种异体反应性T细胞的产生，我们的研究小组也表明LN在 同种异体免疫调节和Treg介导的耐受。这些多方面的功能依赖于LNS AS的性质 具有独特的微血管、间质纤维和间质细胞的高度专门化的器官(称为 成纤维细胞网状细胞[FRCs])。我们最重要的假设是，操纵生物的微环境 LNS将提供一个独特的机会，将同种异体免疫反应引向抗炎耐受。 回应。我们的主要目标是了解支配细胞和分子机制的 LN在免疫激活或耐受诱导过程中的显微解剖适应，并高度发展 创新的治疗策略，促进调节LN微环境并导致免疫 宽容。这个PPG提出了一个连接两个团队(Abdi博士和Bromberg博士)的平台 在LN同种免疫生物学方面的互补技能和专业知识。项目1将测试假设 同种异体免疫期间LN FRC的持续激活将导致FRC向促炎转化 肌成纤维细胞在LN内创造炎症环境，从而进一步促进同种异体免疫。我们的 推论是FRCs功能的恢复和LNS的显微解剖将增强 它们的免疫调节功能和促进耐受性。目标1将研究HVEM/LIGH的作用 FRC分化为促炎性肌成纤维细胞的途径，从而产生炎性 在LN微环境中的环境和促进移植免疫。目标2将调查 纤维化的FRC促进LN的促炎反应的机制。目标3将重新编程 通过FRC递送或LN靶向递送衰老抑制剂进一步促进同种异体免疫的LNS基质 宽容。项目2将检验FRC调节LN层粘连蛋白α4：α5(LAMA4/LAMA5)比率的假设 并控制免疫反应的命运。目标1将定义基质细胞在控制 LAMA4和LAMA5的平衡。目标2将LTβR定义为调节形成的关键途径 LAMA5。AIM 3将使用靶向向LN递送抗CD40L和抗LAMA5单抗来促进 宽容。行政核心(核心A)、纳米颗粒和FRC核心(核心B)将提供 支持这两个项目的基础设施和资源。这些完美集成的和 高度协同的项目和核心是生成变革性的机械数据，这将为 为开发具有高度针对性和创新性的移植治疗策略奠定基础。

项目成果

Chronic rejection as a persisting phantom menace in organ transplantation: a new hope in the microbiota?

• DOI: 10.1097/mot.0000000000000929
• 发表时间: 2021-12-01
• 期刊: Current opinion in organ transplantation
• 影响因子: 2.2
• 作者: Mongodin EF;Saxena V;Iyyathurai J;Lakhan R;Ma B;Silverman E;Lee ZL;Bromberg JS
• 通讯作者: Bromberg JS

Lymph node fibroblastic reticular cells steer immune responses.

• DOI: 10.1016/j.it.2021.06.006
• 发表时间: 2021-08
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: Li L;Wu J;Abdi R;Jewell CM;Bromberg JS
• 通讯作者: Bromberg JS

Intra-Organ Delivery of Nanotherapeutics for Organ Transplantation.

纳米疗法用于器官移植的纳米疗法内递送。

• DOI: 10.1021/acsnano.1c04707
• 发表时间: 2021-11-23
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Hussain, Bilal;Kasinath, Vivek;Madsen, Joren C.;Bromberg, Jonathan;Tullius, Stefan G.;Abdi, Reza
• 通讯作者: Abdi, Reza

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice.

• DOI: 10.1172/jci159672
• 发表时间: 2022-12-15
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Zhao, Jing;Jung, Sungwook;Li, Xiaofei;Li, Lushen;Kasinath, Vivek;Zhang, Hengcheng;Movahedi, Said N.;Mardini, Ahmad;Sabiu, Gianmarco;Hwang, Yoonha;Saxena, Vikas;Song, Yang;Ma, Bing;Acton, Sophie E.;Kim, Pilhan;Madsen, Joren C.;Sage, Peter T.;Tullius, Stefan G.;Tsokos, George C.;Bromberg, Jonathan S.;Abdi, Reza
• 通讯作者: Abdi, Reza

Kidney-Draining Lymph Node Fibrosis Following Unilateral Ureteral Obstruction.

• DOI: 10.3389/fimmu.2021.768412
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Li X;Zhao J;Naini SM;Sabiu G;Tullius SG;Shin SR;Bromberg JS;Fiorina P;Tsokos GC;Abdi R;Kasinath V
• 通讯作者: Kasinath V