A novel in vitro model of thyroid ophthalmopathy

一种新型的甲状腺眼病体外模型

• 批准号: 6739001
• 负责人: Steven E Feldon
• 金额: $ 15.75万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6739001
• 关键词: Graves disease; T cell receptor; T lymphocyte; antigen presenting cell; blood chemistry; cell cell interaction; cell proliferation; clinical research; cytokine; disease /disorder model; fibroblasts; flow cytometry; helper T lymphocyte; human subject; leukocyte activation /transformation; molecular pathology; pathologic process; thyroid disorder; tissue /cell culture

DESCRIPTION (provided by applicant): Thyroid-associated ophthalmopathy (TAO) is the most commonly encountered orbital disease, affecting vision and producing disfigurement. We are beginning to explore an in vitro model of TAO based upon a new methodology of reverse autologous mixed cell reaction (rAMCR), which studies the effects of autologous T-cells from TAO patients on DNA synthesis in orbital fibroblasts from the same patient. This investigation that should meet the NEI challenge to "yield insight into the initiating events leading to fibroblast activation and tissue remodeling and the cell signaling events that stimulate the trafficking of immunocompetent cells to the orbit". It should also aid in determining the immunologic and hormonal basis for the proliferation and phenotypic alteration of orbital fibroblasts (OF). The purpose of this R03 pilot study application is to further develop this model, including a rigorous evaluation of the immunologic and local environmental mechanisms involved in the enhancement of orbital fibroblast proliferation in the rAMCR. The overall hypothesis to be tested in this proposal is that peripheral blood from TAO patients contains T cells that directly activate OF to enhance fibroproliferation and to drive OF to an activated phenotype and to adipocyte-like cells characteristic of TAO. The two specific aims of the study are to determine 1) which subset(s) of peripheral blood T cells are key for stimulating OF proliferation and activation in vitro and by which means of cell-cell communication is this accomplished? and 2) what are the key functional consequences of activation by peripheral blood T cells? In preliminary studies, we have shown that an enriched T-cell results in a two-to-three fold HLA DRII and CD40/CD 40 ligand dependent increase in fibroproliferation. Understanding which OF subset is the target of the rAMCR will help narrow the avenues for therapeutic exploration and will define the cellular cross-talk between immune cells and OF. The nature of the OFs is of critical importance in TAO as they are the effector cells that cause the tissue pathology, including the accumulation of fatty tissue (especially early in disease) and the muscle fibrosis that occurs later. Exploration of the rAMCR model will help move the TAO field forward and will lead to new insights into the pathophysiology of the disease and identification of target molecules the may serve as a basis for possible therapeutic intervention.

描述(申请人提供)：甲状腺相关眼病(TAO)是最常见的眼眶疾病，影响视力和产生毁容。我们正在探索一种基于反向自体混合细胞反应(RAMCR)的TAO体外模型，研究TAO患者自体T细胞对同一患者眼眶成纤维细胞DNA合成的影响。这项研究应满足NEI的挑战，以“深入了解导致成纤维细胞激活和组织重塑的启动事件，以及刺激免疫活性细胞向轨道运输的细胞信号事件”。它还有助于确定眼眶成纤维细胞(OF)增殖和表型改变的免疫学和激素基础。R03先导性研究应用的目的是进一步发展这一模型，包括对rAMCR中促进眼眶成纤维细胞增殖所涉及的免疫学和局部环境机制进行严格评估。这项建议中要检验的总体假设是，TAO患者的外周血中含有T细胞，它们直接激活或促进纤维增殖，并驱动TAO特有的活化表型和脂肪细胞样细胞。这项研究的两个具体目的是确定1)外周血T细胞的哪个亚群(S)是刺激体外增殖和激活的关键，这是通过什么细胞-细胞交流方式实现的？2)外周血T细胞活化的关键功能后果是什么？在初步研究中，我们已经证明，浓缩的T细胞导致两到三倍的HLADriI和CD40/CD40配体依赖的纤维增殖增加。了解哪个亚群是rAMCR的靶点将有助于缩小治疗探索的途径，并将定义免疫细胞和rAMCR之间的细胞串扰。在TAO中，OFs的性质至关重要，因为它们是导致组织病理的效应细胞，包括脂肪组织的堆积(特别是在疾病早期)和后来发生的肌肉纤维化。RAMCR模型的探索将有助于推动TAO领域的发展，并将导致对该病病理生理学的新见解，并识别靶分子，可能作为可能的治疗干预的基础。