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.

尽管免疫抑制和roufine PRA筛查得到了改善，但同种抗体（alloAb）介导了免疫抑制， 显著比例的急性同种异体移植排斥反应发作，并有助于慢性排斥反应的发展。 排斥反应致病性同种抗体的产生需要B细胞和辅助性CD 4 T细胞之间的相互作用 对供体抗原有特异性的细胞通常，这种帮助发生在次级淋巴细胞内的生发中心， 它依赖于CD 40/CD 154共刺激途径。然而，许多人的T细胞库 人类含有对免疫抑制或免疫刺激具有抗性的同种异体记忆T细胞， 封锁我们的初步数据表明，供体反应性记忆CD 4 T细胞诱导更高滴度的alloAb， 与初始CD 4 T细胞相比，即使在没有常规生发中心形成的情况下， CD 40/CD 154相互作用。然而，观察到的高alloAb滴度以及 记忆性CD 4 T细胞帮助的解剖部位和分子要求是未知的，需要 得到考验本研究的目的是确定记忆性CD 4 T细胞的功能表型，为免疫治疗提供帮助。 alloreacfive B细胞和调查的特点和要求，这种帮助。我们有 开发了一种小鼠肾移植模型，以研究 记忆性CD 4 T细胞我们假设，与幼稚细胞相比，记忆性CD 4 T细胞诱导增强， GC的发育和B细胞的更大增殖，促进具有更高亲和力的alloAb的产生 并诱导长寿命抗体分泌浆细胞和记忆B的发育增强 细胞我们进一步提出，虽然滤泡辅助记忆T细胞在诱导alloAb方面具有上级优势， 与其他谱系相比，记忆性CD 4 T细胞的帮助可以发生在典型的生殖细胞之外。 中心，并可通过替代分子途径绕过CD 40/CD 154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： 目标1.探讨供体特异性记忆诱导小鼠产生上级同种抗体的机制 CD 4 T细胞对同种异体肾移植的反应目标2.识别记忆性CD 4 T细胞的功能表型 可为肾移植后同种抗体的产生提供帮助。目标3.确定 记忆CD 4 T细胞为同种抗体产生提供帮助的位置和分子要求。