REGULATORY T AND B CELL CIRCUITS IN TRANSPLANTATION

根据我们在犬类和人类身上所做的几项观察，我们打算 阐明人类B和T细胞网络如何通过自身调节发挥作用 在被感染后产生长期免疫抑制状态的反应 被鼠抗CD3(OKT3)单抗(Ab)治疗所干扰 或使用抗其他T细胞表位或淋巴因子的单抗。我们计划 扩增并分离这种自持性自身免疫抑制因子 对T细胞上相同(自身)标志物的反应性 小鼠单抗的配体(S)。我们还积累了共同的证据 表位存在于T细胞上，这是两种免疫反应的共同特征 器官移植和对T细胞的自身反应性，一种常见的 巨细胞病毒感染和病毒诱导的淋巴增生性疾病的特征 移植受者的紊乱，是这种交叉反应或 抗原模仿，多次涉及网络反应被扰乱 单抗网络对人同种异体移植物免疫反应的影响 描述。因此，实验将继续在犬模型中进行。 纯化的丹参混悬液对T细胞的体外淋巴细胞增殖反应 肾小管细胞和胰岛细胞，后者 补充我们最近重新启动的胰岛临床试验 I型糖尿病患者的移植治疗。重组DNA与免疫化学 将利用技术来定义这些反应的标称抗原 (诱导肾脏细胞反应的组织所特有的多肽 插入II类MHC裂隙的管状细胞和胰岛细胞 分子)。重组技术还将用于生成 上调Ⅱ类MHC表达的细胞因子犬干扰素-γ (干扰素-γ)。将继续产生抗犬细胞因子单抗 以便在这些体外散文中测试它们。使用这些单抗进行治疗将 在我们的胰岛和肾移植模型中继续产生 包括使用新产生的抗犬干扰素-伽马单抗和计划 产生抗犬肿瘤坏死因子-α单抗以供递送 局部(对于胰岛为门内或直接通过动脉 肾移植中的同种异体肾移植)与系统性的，在 努力将这种疗法推广到临床胰岛和肾移植。 后一项研究将包括以下问题：抗细胞因子单抗 导致激活或失活的一般网络响应 细胞因子通过触发或阻断细胞表面受体而发挥作用 抗独特型抗体，推测为原始细胞因子的内部图像 莱兰德。整个实验计划将包括：A)研究B和T 体外和体外细胞机制：b)重组DNA/RNA技术 确定免疫球蛋白基因表达的共性，以及 定义多肽配体的通用编码材料，将它们转移到 通常不表达的原核和真核宿主细胞系和 它们参与特定的分子随机细胞免疫铰链和 功能分析。

Base on several observations we have made in canines and humans we intend to clarify how human B and T cell networks can act by autoregulatory reactions to produce a prolonged immunosuppressed state after being perturbed by therapy with murine anti-CD3 (OKT3) monoclonal antibody (Ab) or with MAbs against other T Cell epitopes or lymphokines. We plan to amplify and isolate this self-perpetuating auto-immunosuppressive reactivity against the same (self) markers on T cells which were the ligands(s) of the murine MAb. We have also accumulated evidence that common epitopes exist on T cells, a common feature of both immune reactivity to organ transplants and that auto-reactivity against T cells, a common feature of both CMV infections and viral induced lymphoproliferative disorders in transplant recipients, is a function this crossreactivity or antigenic mimicry, many times involving network reactions perturbed by monoclonal anti-network influences on the human allograft response just described. Therefore, experiments will continue in the canine model of in vitro T cell lymphoproliferative reactions to purified suspensions of kidney tubular cells and cells from Islets of Langerhans, the latter complementing our clinical trial recently reinstituted of islet transplantation in type I diabetes. Recombinant DNA and immunochemical techniques will utilized to define the nominal antigens of these reactions (the peptides unique to tissues inducing the cellular responses to kidney tubular and islet cells that are inserted in the cleft of the class II MHC molecules). Recombinant techniques will also be used to generate the upregulating cytokine of class II MHC expression, canine interferon-gamma (IFN-gamma). Anti-canine cytokine MAbs will continue to be engendered in order to test them in these ex vivo essays. Therapy with these MAbs will continue to be engendered in our islet and renal transplantation model to include the use of a newly generated anti-canine IFN-gamma MAb and the plan to generate anti-canine tumor necrosis factor-alpha MAb to be delivered locally (intraportally in the case of islets or directly via the artery into the renal allograft in renal transplantation) vs systemically, in an effort to extend such therapy to clinical islet and renal transplantation. This latter study will include the question whether anti-cytokine MAbs genera network responses that cause activation or inactivation of the cytokine effects by triggering or blocking the cell surface receptor by anti-idiotype Abs, the putative internal images of the original cytokine ligand. The overall experimental plan will entail: a) studies of B and T cell mechanisms in vitro and in vitro:b) recombinant DNA/RNA technique to determine the commonality of immunoglobulin gene expression, as well as to define common code material for the peptide ligands, their transfer into ordinarily non-expression procaryotic and eucaryotic host cell lines and their participation in specific molecular rand cellular immune hinging and functional assays.