MODULATION OF CD2 FUNCTION IN TRANSPLANTATION

移植中 CD2 功能的调节

• 批准号: 2067566
• 负责人: Jonathan S Bromberg
• 金额: $ 5.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2067566
• 关键词: CD2 molecule; antibody specificity; antireceptor antibody; biological signal transduction; cell adhesion; cytotoxic T lymphocyte; dosage; gene expression; immunoglobulin isotypes; immunosuppressive; laboratory mouse; leukocyte adhesion molecules; monoclonal antibody; receptor binding; recombinant proteins; tissue /cell culture; transplantation immunology

The major objective is the development of methods and reagents to modulate CD2 function to alter transplant immunity and prolong allograft survival. CD2 is important during the initial interaction of a T cell with antigen presenting membranes and serves three important roles at that time. First, CD2 functions as an adhesion molecule to strengthen intercellular interactions. Second, CD2 is a transmembrane signal transducer and provides messages to the cytoplasm. In some instances these are negative regulatory messages which impede activation. Third, CD2 associates with other surface receptors by sharing subunits, sharing second messenger pathways, or modifying the biochemical function of these receptors. The hypothesis is that by interfering with these roles of CD2, suboptimal antigen recognition will ensue. A reagent which modifies CD2 function may result not only in the failure to recognize antigen and immunologic silence, but also has the potential to induce tolerance and suppression. The first specific aim is to define methods to modulate CD2 function to prolong allograft survival. Aim 1A. Anti-CD2 mAbs will be used to prolong allograft survival in mice. Issues relating to epitope recognition, antibody isotype, dosing regimens, and mAb administered remote from transplantation require evaluation in order to expand and refine the use of anti-CD2 mAbs during allografting. Aim 1B. Soluble CD2 constructs (sCD2) produced in the baculovirus expression vector will be administered to prolong allograft survival. Comparisons of monovalent and polyvalent sCD2 and intact or fragmented anti-CD2 mAbs will help differentiate between adhesion and signaling functions of CD2 in vivo. The use of a novel agent such as CD2 will also provide information on the role of LFA-3 in immunity. Aim 1C. Anti-CD2 mAb or sCD2 will be combined with other mAbs to prolong allograft survival or achieve tolerance. Since CD2 interacts with other surface molecules, altering functions of both molecules may be more effective than modulating each molecule alone. The second specific aim is to define suppressor cells generated by anti-CD2 mAb. Anti-CD2 mAbs induce a negative regulatory subset of lymphocytes which require detailed phenotypic evaluation, assessment of the relative roles of antigen and mAb in their induction, and assessment of mechanism of suppression. The results may influence the immunosuppressive regimens examined in Aim 1A. The third specific aim is to define the determinants and consequences of down modulation of cell surface CD2. Anti-CD2 mAb induces down modulation of CD2 without affecting CD3, CD4, and CD8. The co-signals important for down modulation and the effects on other surface receptors are not currently known. The results will bear directly on the specificity of mAbs selected for Aim 1C and the immunosuppressive regimens examined in Aim 1A.

主要目的是开发方法和试剂 调节CD2功能以改变移植免疫和延长同种异体移植 生存。 在T细胞的初始相互作用中，CD2很重要 抗原呈现膜，并在 那个时候。 首先，CD2用作加强的粘附分子 细胞间相互作用。 第二，CD2是跨膜信号 传感器并向细胞质提供消息。 在某些情况下 这些是阻碍激活的负调节信息。 第三， CD2通过共享亚基与其他表面受体相关联，共享 第二使者途径，或修改这些途径的生化功能 受体。 假设是通过干扰这些角色 CD2，次优抗原识别将发生。 修改的试剂 CD2功能不仅可能导致无法识别抗原和 免疫沉默，但也有可能诱导耐受性和 抑制。 第一个具体目的是定义调制CD2的方法 延长同种异体移植生存的功能。 目标1a。 抗CD2 mAb将是 用于延长小鼠的同种异体移植存活。 与表位有关的问题 识别，抗体同种型，给药方案和MAB 远离移植需要评估才能扩展和 在同种异体过程中，优化使用抗CD2 mAb。 目标1B。 可溶 杆状病毒表达载体中产生的CD2构建体（SCD2）将 用于延长同种异体移植存活。 单价的比较 多价SCD2以及完整或碎片的抗CD2 mAb将有助于 区分CD2在体内的粘附和信号传导函数。 诸如CD2之类的新型代理的使用还将提供有关 LFA-3在免疫中的作用。 AIM 1C。 抗CD2 mAb或SCD2将是 与其他mAb结合以延长同种异体移植生存或达到 宽容。 由于CD2与其他表面分子相互作用，因此改变 这两个分子的功能可能比调节每个分子更有效 单独分子。 第二个特定目的是定义抑制细胞 由抗CD2 mAb产生。 抗CD2 mAb诱导负调节 需要详细表型评估的淋巴细胞的子集， 评估抗原和mab在诱导中的相对作用， 和评估抑制机制。 结果可能会影响 在AIM 1A中检查的免疫抑制方案。 第三个特定 目的是定义下调调制的决定因素和后果 细胞表面CD2。 抗CD2 MAB诱导CD2的调制 影响CD3，CD4和CD8。 共同信号对下降很重要 当前，调节和对其他表面受体的影响 已知。 结果将直接依赖于mAb的特异性 选择用于AIM 1C和AIM检查的免疫抑制方案 1a。