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 器官移植仍然是最终器官疾病患者的主要治疗策略。之一 改善长期移植结果的最高未满足需要是设计更有效的免疫力 调制。这需要对移植同种异体免疫的创新机械研究。淋巴结（LN）为 同种免疫的典型器官。尽管LN中对同种抗原的认可对 同种反应性T细胞的产生，我们的小组还表明，LN在 同种免疫调节和Treg介导的耐受性。这些多方面的功能基于LN的性质 具有独特微脉管系统，基质纤维和基质细胞的极高专业器官（称为 成纤维细胞网状细胞[FRCS]）。我们的总体假设是操纵微环境 LNS将提供一个独特的机会，将同种异体反应引导到抗炎耐受性 回复。我们的主要目标是了解控制该的细胞和分子机制 在免疫激活或耐受性诱导过程中LN的微解剖学适应，并高度发展 创新的理论策略促进了监管LN微环境并导致免疫力 宽容。该PPG阐明了一个平台，用于将两个团队（Abdi博士和Bromberg博士）与 LN AlloMune-biology中的完全技巧和专业知识。项目1将检验以下假设 同种免疫期间LN的FRC持续激活将导致FRC转化为促炎 肌纤维细胞在LN内形成炎症环境，这将进一步促进同种免疫性。我们的 推论假设是，恢复FRC的功能和LNS的微解剖学将增强 它们的免疫调节功能并促进耐受性。 AIM 1将检查HVEM/LIGHT的作用 将FRC分化为促炎性肌纤维细胞的途径，从而产生炎症 在LN微环境中的环境和促进移植免疫。 AIM 2将调查 纤维化FRC促进LN中促炎反应的机制。 AIM 3将重新编程 通过FRC递送或以LN为目标的传感抑制剂的LN基质，以进一步促进同种免疫 宽容。项目2将测试FRCS调节LN层粘连蛋白α4：α5（LAMA4/LAMA5）比的假设 并控制免疫反应的命运。 AIM 1将定义基质细胞在控制中的作用 LAMA4和LAMA5的平衡。 AIM 2将定义LTβR作为调节形成的关键途径的作用 喇嘛5。 AIM 3将使用针对抗CD40L和抗LAMA5 MABS的有针对性递送向LN促进 宽容。行政核心（核心A）和纳米颗粒和FRC核心（核心B）将提供 基础架构和资源以支持这两个项目。这些良好整合的最终目标和 高度协同的项目和核心是生成变革性的机械数据，这将放置 开发高度针对性和创新的治疗策略的基础。

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.

• 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

ACTH treatment promotes murine cardiac allograft acceptance.

• DOI: 10.1172/jci.insight.143385
• 发表时间: 2021-07-08
• 期刊: JCI insight
• 影响因子: 8
• 作者: Zhao J;Jiang L;Uehara M;Banouni N;Al Dulaijan BS;Azzi J;Ichimura T;Li X;Jarolim P;Fiorina P;Tullius SG;Madsen JC;Kasinath V;Abdi R
• 通讯作者: Abdi R