REGULATORY T AND B CELL CIRCUITS IN TRANSPLANTATION

我们计划利用犬移植模型来研究 名义、特定器官(肾脏和胰腺)的作用，以及 同种异体移植排斥和自身免疫中的MHC抗原。这个 具体目的是：1)产生单抗 专为各种犬淋巴和非骨髓源性 2)研究T细胞的表型和功能特性 来自肾和胰腺排斥反应的细胞系和克隆 关于组织和同种异体特异性反应性的同种异体移植。3)至 MHC分子原位诱导表达过程的研究 体内和体外培养的肾脏(和胰岛)细胞 体外操作；4)A)研究其特点和作用 纯化的犬用干扰素(干扰素-γ)的能力 体外调控MHC等细胞表面表位的表达 B.评价单抗的体外和体内效应 产生了干扰素-伽马抗体。5)在治疗上使用几种 精选的mAbs可促进移植物的接受和调节 自身免疫，或引起排斥反应和诱导自身免疫。这个 狗最近被发现是自然发育的 出现小鼠免疫球蛋白抗体，这一发现类似于分离的 在人类身上的观察。我们最终计划申请 免疫调节网络型协议旨在限制 犬对所用单抗的体液反应 治疗上，即防止产生狗抗鼠 免疫球蛋白抗体，并调节预形成抗体的存在 因此，单抗治疗的免疫学后果可以是 增强版。然而，这项资助中详细说明的实验在 这种免疫调节性抗病毒药物的体外评价 免疫球蛋白等T细胞和B细胞表面靶点 表位(初步数据显示，两种细胞类型都与这些表位结合 抗Ig分子)。抑制(单抗效应)与突破 (抗mAb效应)体外淋巴组织增殖物的实验 提出了相应的反应方案。生物学和临床的相关性 这项建议的意义在于将我们的理解扩大到 治疗性免疫调节实用方法的应用 器官移植与自身免疫性疾病的治疗 导致终末期器官衰竭。免疫生物学的衍生品 可能会澄清我们对网络反馈的理解以及 抗免疫球蛋白抗体在人类免疫缺陷中的作用 免疫调节。

We plan to utilize the canine transplantation model to investigate the role of nominal, organ specific (kidney and pancreas), and MHC antigens in allograft rejection and autoimmunity. The specific aims are to: 1) generate monoclonal antibodies (mAbs) specific for various dog lymphoid and non-bone marrow derived cells; 2) to study phenotypic and functional characterization of T cell lines and clones derived from rejecting renal and pancreatic allografts with regard to tissue and allospecific reactivity. 3) To study the process of induced expression of MHC molecules in situ and on isolated kidney (and pancreatic islet) cells by in vivo and in vitro manipulations; 4) a. to study the characteristics and effects of purified canine gamma interferon (IFN-gamma) in its ability to modulate MHC and other cell surface epitope expression in vitro and in vivo; b. to assess the in vitro and in vivo effects of mAbs generated against IFN-gamma. 5) To therapeutically use several selected mAbs to both facilitate graft acceptance and modulate autoimmunity, or evoke rejection and induce autoimmunity. The dog has been recently found to have preformed naturally occurring antibodies to mouse IgG, a finding similar to isolated observations in the humans. We eventually plan to apply immunoregulatory network type protocols designed to limit the humoral response in the dog to the mAb to be used therapeutically, i.e. to prevent the production of dog anti-mouse Ig antibodies, and modulate the presence of preformed antibodies so that the immunologic consequences of mAb treatment can be enhanced. The experiments detailed in this grant, however, are in vitro assessments of such immunoregulatory anti- immunoglobulins, such as their T cell and B cell surface target epitopes (preliminary data show that both cell types bind these anti-Ig molecules). Inhibition (mAb effect) and breakthrough (anti-mAb effect) experiments of in vitro lymphoproliferative reactions also are proposed. The biological and clinical relevance of this proposal is in expanding our understanding to the point of applying practical methods of therapeutic immunoregulation in organ transplantation and the treatment of autoimmune diseases leading to end-stage organ failure. The spin off in immunobiology may clarify our understanding of network feedback as well as the role of performed anti-immunoglobulin antibodies in immunoregulation.