Reshaping lymph node stroma for transplant tolerance

重塑淋巴结基质以提高移植耐受性

• 批准号: 10662321
• 负责人: Jonathan S Bromberg
• 金额: $ 45.09万
• 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/10662321
• 关键词: Alloantigen; Antibodies; Antigens; Area; Autoimmunity; Blood Vessels; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Maturation; Cell physiology; Chimeric Proteins; Data; Dendritic Cells; Development; Environment; Equilibrium; FOXP3 gene; Formulation; Goals; Graft Rejection; Graft Survival; Graft Tolerance; Heart Transplantation; High Endothelial Venule; Home; Immune response; Immunity; Immunology; Infection; Inflammation; Inflammatory; Investigation; Knock-out; Laboratories; Laminin; Microanatomy; Molecular; Monoclonal Antibodies; Mus; Pathway interactions; Play; Population; Production; Receptor Activation; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Reticular Cell; Role; Shapes; Signaling Molecule; Spleen; Stromal Cells; Structure; T cell differentiation; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Transplantation; Transplantation Tolerance; Vaccination; anergy; cell motility; effector T cell; experience; heart allograft; innovation; knockout gene; laminin alpha5; lymph node medullary portion; lymph node microenvironment; lymph nodes; lymphotoxin beta receptor; migration; mouse model; nanoparticle; neutralizing antibody; programs; receptor; response; single-cell RNA sequencing; targeted delivery; targeted treatment; Alloantigen; Antibodies; Antigens; Area; Autoimmunity; Blood Vessels; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Maturation; Cell physiology; Chimeric Proteins; Data; Dendritic Cells; Development; Environment; Equilibrium; FOXP3 gene; Formulation; Goals; Graft Rejection; Graft Survival; Graft Tolerance; Heart Transplantation; High Endothelial Venule; Home; Immune response; Immunity; Immunology; Infection; Inflammation; Inflammatory; Investigation; Knock-out; Laboratories; Laminin; Microanatomy; Molecular; Monoclonal Antibodies; Mus; Pathway interactions; Play; Population; Production; Receptor Activation; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Reticular Cell; Role; Shapes; Signaling Molecule; Spleen; Stromal Cells; Structure; T cell differentiation; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Transplantation; Transplantation Tolerance; Vaccination; anergy; cell motility; effector T cell; experience; heart allograft; innovation; knockout gene; laminin alpha5; lymph node medullary portion; lymph node microenvironment; lymph nodes; lymphotoxin beta receptor; migration; mouse model; nanoparticle; neutralizing antibody; programs; receptor; response; single-cell RNA sequencing; targeted delivery; targeted treatment

Project Summary/Abstract My laboratory has contributed chiefly to the better understanding of the mechanisms by which lymph node (LN) stroma controls transplant tolerance. We have devoted much effort to defining specific compartments of the LN where Foxp3+ regulatory T cells (Treg) are induced and activated. We showed that during tolerance induction by costimulatory blockade, naïve T cells migrate to the LN, but not the spleen. During tolerance induction, naïve T cells specifically home to the cortical ridge (CR) of LN, entering via the nearby high endothelial venules (HEV). In the CR they are stimulated by alloantigen-presenting plasmacytoid dendritic cells to differentiate into induced Treg (iTreg). Our data indicate that in tolerogenic conditions iTreg are mostly formed within the CR region, whereas T cells which enter the medulla of LN experience anergy. More specifically, the ratio of stromal laminin α4:α5 (referred to as LAMA4/LAMA5) of the CR region critically determine the response to alloantigen and iTreg formation. A high LAMA4/LAMA5 ratio promotes tolerance, whereas a low LAMA4/LAMA5 ratio promotes transplant immunity. Mechanistically, LAMA4 promotes CD4 migration to the CR, promotes Foxp3 expression and iTreg maturation, and inhibits effector T cell differentiation. In contrast, LAMA5 inhibits migration of CD4 cells into HEV, yet costimulates T cell proliferation and maturation to inflammatory Th17. Abrogating this interaction with neutralizing antibodies enhances iTreg migration to the CR region and significantly prolongs heart allograft survival. Our overall hypothesis is that the LAMA4/LAMA5 ratio of the CR critically determines the fate of iTreg formation and transplant tolerance. Our overall goal is to define the key cellular (FRC) and molecular (LTβR) mechanisms which control the laminin composition of LN and thereby leverage this microstructure to manipulate immunity toward transplant tolerance. To investigate this hypothesis, we propose the following AIMS: Aim 1. Define the role of LN stromal cells in controlling the balance of LAMA4 and LAMA5 during alloimmune responses. Aim 2. Define the role of LTβR activation of FRC as a key pathway in inducing formation of LAMA5. Aim 3. Targeted delivery of costimulatory molecule anti-CD40L mAbs and anti-laminin α5 Abs to the LN to promote tolerance. Overall, key signaling molecules that regulate FRC function to remodel LN laminins and the LAMA4/LAMA5 ratio dictate the immune response toward inflammation and immunity (low ratio) or toward suppression and tolerance (high ratio). These Aims will achieve our overall goal to define the key cellular (FRC) and molecular (LTβR) mechanisms which control the laminin composition of LN. These data lay the groundwork for developing highly innovative targeted therapies to reprogram the microstructure of LN to promote transplant tolerance.

项目摘要/摘要 我的实验室有助于更好地理解淋巴结（LN）的机制 基质控制移植耐受性。我们已经部署了很多努力来定义 LN诱导并激活Foxp3+调节性T细胞（TREG）。我们表明在公差期间 通过共刺激桶，幼稚的T细胞诱导迁移到LN，但不是脾脏。在公差期间 诱导，幼稚的T细胞，专门属于LN皮质脊（CR），通过附近的高高进入 内皮静脉（HEV）。在CR中，它们受到同种抗原的质细胞类树突状细胞的刺激 分化为诱导的treg（itreg）。 我们的数据表明，在耐受性条件下，ITREG主要是在Cr区域内形成的，而T细胞 进入LN的髓质体验不动。更具体地说，基质层粘连蛋白α4：α5的比率（引用） Cr区域的LAMA4/LAMA5）批判性地确定对同种剂和ITREG形成的反应。一个 High Lama4/Lama5比率促进公差，而低喇嘛4/LAMA5比率促进移植 免疫。从机械上讲，Lama4促进CD4迁移到CR，促进Foxp3表达和ITREG 成熟并抑制效应T细胞分化。相反，LAMA5抑制CD4细胞迁移到 HEV，但可以刺激T细胞增殖和成熟到炎症性Th17。废除与 中和抗体增强了ITREG迁移到Cr区域的迁移，并显着延长了同种异体移植 生存。我们的总体假设是，CR的Lama4/Lama5比率批判性地决定了 ITREG形成和移植耐受性。我们的总体目标是定义钥匙细胞（FRC）和分子 （LTβR）控制LN的层粘连蛋白组成，从而利用该微结构的机制 操纵对移植耐受性的免疫力。为了研究这一假设，我们提出以下 目标： AIM 1。定义LN基质细胞在控制LAMA4和LAMA5的平衡中的作用 同种免疫反应。 AIM 2。将LTβR激活的作用定义为在诱导LAMA5形成中的关键途径。 AIM 3。靶向分子抗CD40L mAb和抗层蛋白α5ABS的靶向输送到LN 促进宽容。 总体而言，将FRC功能调节为重塑LN层粘连蛋白和LAMA4/LAMA5的关键信号分子5 比率决定对炎症和免疫组织化学（低比率）的免疫反应或抑制和 公差（高比例）。这些目标将实现我们定义钥匙细胞（FRC）和分子的总体目标 （LTβR）控制LN的层粘连蛋白组成的机制。这些数据为 开发高度创新的靶向疗法以重新编程LN的微观结构以促进移植 宽容。