Memory CD4 T cell driven antibody responses to renal allografts

记忆 CD4 T 细胞驱动的抗体对肾同种异体移植物的反应

• 批准号: 7891954
• 负责人: Anna Valujskikh
• 金额: $ 34.4万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-08 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891954
• 关键词: Acute; Affinity; Allografting; Antibodies; Antibody Formation; Antigens; B Cell Proliferation; B-Lymphocytes; Blood capillaries; Bypass; CD4 Positive T Lymphocytes; Cell Communication; Cells; Characteristics; Chronic; Clinical; Complement; Creatinine; Data; Deposition; Development; Diagnostic; Evaluation; Future; Goals; Graft Rejection; Heart; Heart Transplantation; Human; Immune response; Immunity; Immunoglobulin Class Switching; Immunoglobulin G; Immunosuppression; Incidence; Infiltration; Injury; Investigation; Isoantibodies; Kidney; Kidney Transplantation; Life; Liver; Location; Lung; Lymphoid; Mediating; Memory; Memory B-Lymphocyte; Modeling; Molecular; Mus; Organ; Organ Transplantation; Pathway interactions; Phenotype; Plasma Cells; Process; Production; Property; Reporting; Resistance; Rodent Model; Role; Screening procedure; Serum; Signal Transduction; Spleen; Staging; Structure of germinal center of lymph node; T cell response; T memory cell; T-Lymphocyte; TNFRSF5 gene; Testing; Tissue Grafts; Tissues; Transplant Recipients; Transplantation; Work; allograft rejection; capillary; design; graft function; heart allograft; high risk; improved; insight; kidney allograft; memory CD4 T lymphocyte; molecular site; mouse model; pancreas allograft; prevent; programs; response; trafficking

Despite improved immunosuppression and roufine PRA screening, alloreacfive anfibodies (alloAb) mediate a significant proportion of acute allograft rejection episodes and contribute to the development of chronic rejection. Production of pathogenic alloAb isotypes requires interactions between B cells and helper CD4 T cells specific for donor anfigens. Typically, this help occurs in germinal centers within secondary lymphoid organs and is dependent on CD40/CD154 cosfimulatory pathway. However, the T cell repertoire of many humans contains alloreacfive memory T cells that are resistant to immunosuppression or cosfimulatory blockade. Our preliminary data show that donor-reactive memory CD4 T cells induce higher titers of alloAb compared to naive CD4 T cells even in the absence of conventional germinal center formafion and CD40/CD154 interacfion. However, the mechanisms underiying the observed high alloAb titers as well as anatomical sites and molecular requirements of help by memory CD4 T cells are sfill unknown and need to be tested. The goal of this study is to identify functional phenotype of memory CD4 T cells providing help for alloreacfive B cells and to investigate the characteristic features and requirements for this help. We have developed a mouse model of kidney transplantation to study donor-specific alloAb responses induced by memory CD4 T cells. We hypothesize that compared to naive cells, memory CD4 T cells inifiate enhanced development of GCs and greater proliferation of B cells, promote production of alloAb with higher affinifies for donor antigens and induce enhanced development of long-lived Ab secrefing plasma cells and memory B cells. We further propose that while follicular helper memory T cells are superior in inducing alloAb responses compared to other lineages, help by memory CD4 T cells can occur outside of typical germinal centers and can bypass the requirement for CD40/CD154 interacfion via alternative molecular pathways such as TLR and BAFF/APRIL signaling. We will test this hypothesis in three Specific Aims: Aim 1. To investigate the mechanisms of superior alloantibody production induced by donor-specific memory CD4 T cells in response to renal allografts. Aim 2. To identify functional phenotype of memory CD4 T cells capable of providing help for alloantibody production after renal allograft placement. Aim 3. To determine the location and molecular requirements of help provided by memory CD4 T cells for alloantibody production.

尽管免疫抑制得到改善并进行常规 PRA 筛查，同种异体反应性抗体 (alloAb) 仍然介导 急性同种异体移植排斥反应的比例很大，并有助于慢性排斥反应的发展 拒绝。致病性同种抗体同种型的产生需要 B 细胞和辅助 CD4 T 之间的相互作用 对供体抗原具有特异性的细胞。通常，这种帮助发生在次级淋巴内的生发中心 器官，并且依赖于 CD40/CD154 共刺激途径。然而，许多 T 细胞库 人类含有同种反应性记忆 T 细胞，可抵抗免疫抑制或共刺激 封锁。我们的初步数据表明，供体反应性记忆 CD4 T 细胞诱导更高滴度的同种抗体 与初始 CD4 T 细胞相比，即使在没有常规生发中心形成的情况下， CD40/CD154 相互作用。然而，观察到的高同种抗体滴度的机制以及 记忆 CD4 T 细胞的解剖部位和分子需求尚不清楚，需要 被测试。本研究的目的是确定记忆 CD4 T 细胞的功能表型，为 同种反应性 B 细胞并研究其特征和要求对此有帮助。我们有 开发了一种肾移植小鼠模型来研究供体特异性同种抗体反应 记忆 CD4 T 细胞。我们假设与初始细胞相比，记忆 CD4 T 细胞启动增强 GC 的发育和 B 细胞的更大增殖，促进具有更高亲和力的同种抗体的产生 供体抗原并诱导长寿命抗体分泌浆细胞和记忆 B 的增强发育 细胞。我们进一步提出，虽然滤泡辅助记忆 T 细胞在诱导 alloAb 方面更胜一筹 与其他谱系相比，在记忆 CD4 T 细胞的帮助下，反应可以发生在典型的生发细胞之外 中心并可以通过替代分子途径绕过 CD40/CD154 相互作用的要求 例如 TLR 和 BAFF/APRIL 信令。我们将在三个具体目标中检验这一假设： 目的 1. 研究供体特异性记忆诱导产生优质同种抗体的机制 CD4 T 细胞对肾同种异体移植物的反应。目标 2. 鉴定记忆 CD4 T 细胞的功能表型 能够为同种异体肾移植术后产生同种抗体提供帮助。目标 3. 确定 记忆 CD4 T 细胞为同种抗体产生提供帮助的位置和分子要求。