ACTIVATION/APATHY/ANERGY/APOPTOSIS IN TRANSPLANTATION

移植中的激活/冷漠/无能/细胞凋亡

• 批准号: 6328745
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 58.23万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6328745
• 关键词: B lymphocyte; CD28 molecule; CD40 molecule; CD95 molecule; anergy; apoptosis; biological signal transduction; biological transport; cell adhesion molecules; cellular immunity; chemical kinetics; cytotoxic T lymphocyte; gene expression; genetic regulation; helper T lymphocyte; histocompatibility; homologous transplantation; humoral immunity; intermolecular interaction; laboratory mouse; leukocyte activation /transformation; macrophage; tissue /cell culture; transplant rejection; transplantation immunology; vascular endothelium

Activated T cells play a pivotal role in allograft rejection. Upon activation T cells express gp39 a member of the TNF cytokine superfamily. CD40, the receptor for gp39 is expressed on a wide variety of cells, including dendritic cells, B cells, macrophages, endothelial cells (EC), and T cells. Evidence for the crucial role of gp39 in humoral immunity came from the recognition that the hyperIgM syndrome results from a defect in the gp39 gene. In addition, it has become increasingly apparent that CD4O also plays an important role in the regulation of macrophage, dendritic cell, EC and T cell function. Our central hypothesis is that the CD4O pathway plays a crucial role in the transition between the afferent and efferent phases of allograft rejection. In particular, CD40/gp39 signals are necessary for the delivery of cognate T cell help for effector cell activation and for T cell clonal expansion. We will address this hypothesis in the following specific aims: i) To define the kinetics and distribution of CD4O and gp39 expression during. allograft rejection. 2) To study the role of CD40/gp39 interactions in the T-dependent macrophage activation. Our hypothesis being that CD4O signals delivered during cognate interactions with T cells activate macrophage to express effector molecules and to exhibit effector functions. 3) To study the role of CD4O/gp39 interactions in the regulation of EC activation and leukocyte traffic during allograft rejection. We will test the hypothesis that CD4O/gp39 interactions play a critical role in the regulation of lymphocyte recruitment into allografts. 4) To study the role of CD40/gp39 interactions in the regulation of T cell clonal expansion. We hypothesize that CD4O signals antagonize pro-apoptotic signals delivered via the fas pathway. Deprivation of CD4O signals during T cell responses allows fas signals to predominate, leading to "premature" activation-induced apoptosis, aborting clonal expansion. 5) To explore the mechanisms by which CTLA4-Ig and anti-gp39 synergize to inhibit allo-immune responses. Our hypothesis is that simultaneous blockade of CD28 and CD4O signals during antigen-challenge further shifts the balance toward accelerated fas-mediated activation-induced apoptosis. The CD4O pathway is distinct from other pathways previously targeted to inhibit allograft rejection. Unlike other agents anti-gp39 mAbs are not potent inhibitors of T cell activation. Rather CD4O appears to be a pivotal molecule in the transition from the afferent to the efferent phase of immune responses. As a regulator of many facets of T-dependent immune responses including T cell help for B cell, macrophage and EC activation, as well as T cell clonal expansion, further understanding the biology of the CD4O pathway promises to yield a new class of agents to therapeutically manipulate immune responses.

活化的T细胞在同种异体移植排斥反应中起关键作用。后 活化T细胞表达TNF细胞因子成员gp 39 超家族CD 40是gp 39的受体，在多种细胞上表达。 细胞，包括树突状细胞、B细胞、巨噬细胞、内皮细胞 细胞（EC）和T细胞。gp 39的关键作用的证据 体液免疫来自于高IgM综合征 是由gp 39基因缺陷引起的。此外，它还成为 越来越明显的是，CD 4 O也发挥着重要作用， 调节巨噬细胞、树突状细胞、EC和T细胞功能。 我们的中心假设是，CD 4 O途径发挥了至关重要的作用， 在同种异体移植物的传入和传出相之间的过渡中 排斥反应 特别地，CD 40/gp 39信号对于免疫应答是必需的。 递送同源T细胞有助于效应细胞活化和 T细胞克隆扩增。我们将在下面的文章中讨论这个假设： （一）确定下列物质的动力学和分布： CD 40和gp 39的表达。同种异体移植排斥反应。2)研究 CD 40/gp 39相互作用在T细胞依赖性巨噬细胞中的作用 activation.我们的假设是，CD 4 O信号在 与T细胞的同源相互作用激活巨噬细胞表达 效应分子并表现出效应功能。 3)研究 CD 4 O/gp 39相互作用在EC活化调节中的作用， 同种异体移植排斥反应中的白细胞运输。我们将测试 假设CD 4 O/gp 39相互作用在 调节淋巴细胞募集到同种异体移植物中。4)研究 CD 40/gp 39相互作用在T细胞克隆形成调控中的作用 扩张.我们假设CD 4 O信号拮抗促凋亡 通过Fas途径传递的信号。 CD 4 O信号的检测 在T细胞应答过程中，Fas信号占主导地位，导致 “过早”激活诱导的细胞凋亡，中止克隆扩增。 5)探讨CTLA 4-IG与抗gp 39协同作用的机制 抑制同种免疫反应 我们的假设是 在抗原攻击期间阻断CD 28和CD 40信号进一步 使平衡向加速Fas介导的激活诱导的 凋亡 CD 4 O途径与以前靶向的其他途径不同 抑制同种异体移植排斥反应。 与其他试剂不同，抗gp 39 mAb是 而不是T细胞活化的有效抑制剂。 而CD 4 O似乎是 从传入神经到传出神经的关键分子 免疫反应阶段。作为T依赖的许多方面的调节剂， 免疫应答包括T细胞辅助B细胞、巨噬细胞和EC 激活，以及T细胞克隆扩增，进一步了解 CD 4 O途径的生物学有望产生一类新的药物 来治疗性地操纵免疫反应。