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: 10224026
• 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/10224026
• 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.

项目总结/摘要 我的实验室主要有助于更好地理解淋巴结（LN） 基质控制移植耐受性。我们已经投入了大量的精力来确定 LN，其中Foxp 3+调节性T细胞（Treg）被诱导和活化。我们发现在耐受期 通过共刺激阻断诱导，幼稚T细胞迁移到LN，但不迁移到脾脏。公差期间 在诱导过程中，幼稚T细胞特异性地归巢于LN的皮质嵴（CR），通过附近的高密度脂蛋白（HDL）进入。 内皮小静脉（HEV）。在CR中，它们受到同种异体抗原呈递浆细胞样树突状细胞的刺激 以分化成诱导性Treg（iTreg）。 我们的数据表明，在致耐受性条件下，iTreg主要在CR区域内形成，而T细胞主要在CR区域内形成。 进入LN髓质的神经元无反应性。更具体地说，基质层粘连蛋白α4：α5的比率（参考 CR区的LAMA 4/LAMA 5）关键性地决定对同种异体抗原的应答和iTreg形成。一 高LAMA 4/LAMA 5比率促进耐受性，而低LAMA 4/LAMA 5比率促进移植 免疫力在机制上，LAMA 4促进CD 4迁移至CR，促进Foxp 3表达和iTreg表达。 成熟，并抑制效应T细胞分化。相比之下，LAMA 5抑制CD 4细胞迁移到 HEV，但共刺激T细胞增殖和成熟为炎性Th 17。取消这种互动与 中和抗体增强iTreg向CR区域的迁移，并显著抑制心脏同种异体移植物 生存我们的总体假设是，CR的LAMA 4/LAMA 5比率决定了CR的命运。 iTreg形成和移植耐受性。我们的总体目标是确定关键的细胞（FRC）和分子 (LTβR）机制，其控制LN的层粘连蛋白组成，从而利用这种微结构， 操纵免疫力使之对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.确定LN基质细胞在控制LAMA 4和LAMA 5平衡中的作用， 同种免疫反应 目标二。确定FRC的LTβR活化作为诱导LAMA 5形成的关键途径的作用。 目标3.共刺激分子抗CD 40 L单克隆抗体和抗层粘连蛋白α5单克隆抗体靶向治疗LN的研究 促进宽容。 总之，调节FRC功能的关键信号分子重塑LN层粘连蛋白和LAMA 4/LAMA 5， 比率决定了对炎症和免疫（低比率）或对抑制的免疫应答， 高比率（High Ratio）。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）机制控制LN的层粘连蛋白组成。这些数据奠定了基础， 开发高度创新的靶向疗法，重新编程LN的微观结构，以促进移植 宽容