REGULATORY T AND B CELL CIRCUITS IN TRANSPLANTATION

移植中的 T 细胞和 B 细胞调节回路

• 批准号: 3227325
• 负责人: Joshua Miller
• 金额: $ 28.19万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3227325
• 关键词: B lymphocyte; Herpesviridae disease; affinity chromatography; antiidiotype antibody; autoantibody; autoimmune disorder; cellular immunity; clone cells; cross immunity; cytokine; cytomegalovirus; dogs; gene expression; histochemistry /cytochemistry; histocompatibility; histocompatibility antigens; immunochemistry; immunoglobulins; immunopharmacology; immunosuppression; interferons; kidney transplantation; laboratory mouse; leukocyte activation /transformation; molecular cloning; monoclonal antibody; pancreas transplantation; radiotracer; recombinant DNA; surface antigens; tumor necrosis factor alpha; virus protein

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.

基于我们在犬类和人类中的几项观察， 为了阐明人类B和T细胞网络如何通过自动调节 免疫反应，以产生长期的免疫抑制状态后， 受鼠抗CD 3（OKT 3）单克隆抗体（Ab）治疗干扰 或与抗其它T细胞表位或淋巴因子的MAb结合。我们计划 放大并分离出这种自我维持的自身免疫抑制 对T细胞上相同（自身）标记物的反应性， 小鼠MAb的配体。我们也积累了证据， 表位存在于T细胞上，这是免疫反应性对 器官移植和针对T细胞的自身反应，一种常见的 CMV感染和病毒诱导的淋巴组织增生的特征 在移植受者的疾病，是一个功能，这种交叉反应性或 抗原模拟，很多时候涉及网络反应， 单克隆抗网络对人类同种异体移植反应的影响 介绍了因此，实验将继续在犬模型中进行。 体外T细胞淋巴增殖反应的纯化悬浮液 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 I型糖尿病的治疗重组DNA和免疫化学 技术将用于确定这些反应的标称抗原 (the组织特有的肽诱导细胞对肾脏的反应 插入II类MHC裂隙中的小管和胰岛细胞 分子）。重组技术也将用于产生 上调II类MHC表达的细胞因子，犬干扰素-γ （IFN-γ）。抗犬细胞因子单克隆抗体将继续产生， 以便在这些体外试验中测试它们。用这些单克隆抗体治疗将 在我们的胰岛和肾移植模型中， 包括使用新产生的抗犬IFN-γ单克隆抗体， 以产生待递送的抗犬肿瘤坏死因子α单克隆抗体， 局部（在胰岛的情况下门静脉内或直接通过动脉 在肾移植中移植入同种异体肾）与全身， 努力将这种治疗扩展到临床胰岛和肾移植。 后一项研究将包括抗细胞因子单克隆抗体是否 产生网络反应，导致激活或失活的 通过触发或阻断细胞表面受体， 抗独特型抗体，原始细胞因子的假定内部图像 配体。总体实验计划将包括：a）对B和T的研究 体外和体外的细胞机制：B）重组DNA/RNA技术， 确定免疫球蛋白基因表达的共性，以及 定义肽配体的共同编码物质，它们转移到 通常不表达的原核和真核宿主细胞系， 它们参与特异性分子兰德细胞免疫铰链， 功能测定