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: 10431927
• 负责人: Jonathan S Bromberg
• 金额: $ 46.35万
• 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/10431927
• 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; 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; 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; 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.

项目概要/摘要 我的实验室主要致力于更好地了解淋巴结 (LN) 的机制 基质控制移植耐受。我们投入了大量精力来定义特定的隔间 LN，Foxp3+ 调节性 T 细胞 (Treg) 被诱导和激活。我们表明，在耐受期间 通过共刺激阻断诱导，幼稚 T 细胞迁移至淋巴结，但不迁移至脾脏。耐受期间 诱导后，幼稚 T 细胞专门定位于 LN 的皮质脊 (CR)，通过附近的高位进入 内皮微静脉（HEV）。在 CR 中，它们受到同种异体抗原呈递的浆细胞样树突状细胞的刺激 分化为诱导性 Treg (iTreg)。 我们的数据表明，在耐受条件下，iTreg 大部分在 CR 区域内形成，而 T 细胞 进入 LN 髓质的部分经历无能。更具体地说，基质层粘连蛋白 α4:α5 的比例（称为 CR 区域的 LAMA4/LAMA5）关键决定对同种异体抗原和 iTreg 形成的反应。一个 高LAMA4/LAMA5比率促进耐受，而低LAMA4/LAMA5比率促进移植 免疫。从机制上讲，LAMA4 促进 CD4 迁移至 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 细胞迁移至 HEV，但共刺激 T 细胞增殖并成熟为炎症性 Th17。取消这种互动 中和抗体增强 iTreg 迁移至 CR 区域并显着延长同种异体心脏移植时间 生存。我们的总体假设是 CR 的 LAMA4/LAMA5 比率关键决定了 iTreg 形成和移植耐受。我们的总体目标是定义关键的细胞（FRC）和分子 (LTβR) 机制控制 LN 的层粘连蛋白组成，从而利用这种微观结构 操纵免疫以实现移植耐受。为了研究这一假设，我们提出以下建议 目标： 目标 1. 明确 LN 基质细胞在控制 LAMA4 和 LAMA5 平衡的作用 同种免疫反应。 目标 2. 确定 FRC 的 LTβR 激活作为诱导 LAMA5 形成的关键途径的作用。 目标 3. 将共刺激分子抗 CD40L mAb 和抗层粘连蛋白 α5 Ab 靶向递送至 LN 以促进宽容。 总体而言，调节 FRC 功能以重塑 LN 层粘连蛋白和 LAMA4/LAMA5 的关键信号分子 比率决定了对炎症和免疫（低比率）或抑制和免疫的免疫反应 公差（高比率）。这些目标将实现我们的总体目标，即定义关键的细胞（FRC）和分子 (LTβR) 控制 LN 层粘连蛋白组成的机制。这些数据奠定了基础 开发高度创新的靶向疗法来重新编程 LN 的微观结构以促进移植 宽容。