Giant cell vasculitis is a T cell-dependent disease
Giant cell vasculitis is a T cell-dependent disease
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DOI：
10.1007/bf03401699
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发表时间：
1997-08-01
影响因子：
5.7
通讯作者：
Weyand, CM
中科院分区：
文献类型：
--
作者：
Brack, A;Geisler, A;Weyand, CM
背景：巨细胞动脉炎（GCA）是一种系统性血管炎，好发于中、大动脉。该综合征的发病机制尚不清楚，并且由于缺乏关于血管壁损伤机制的信息，治疗选择有限。动脉炎致病事件的线索可能来自于对组织浸润细胞功能的了解。GCA的动脉损伤与肉芽肿的形成有关，肉芽肿由T细胞、活化的巨噬细胞和多核巨细胞组成。为了研究T细胞的作用，我们植入发炎的颞动脉与GCA患者严重联合免疫缺陷（SCID）小鼠和研究是否血管病变T细胞dependent.Materials和方法：颞动脉标本与GCA患者植入到SCID小鼠。通过双色免疫组织化学比较从小鼠取回的新鲜动脉和移植物的组织形态学外观，并通过半定量细胞因子转录与基于聚合酶链反应（PCR）的测定系统分析组织浸润细胞的功能概况。通过使用T细胞受体β链特异性PCR随后测序来评估组织浸润性T细胞库中显性T细胞群体的存在。为了研究T细胞在组织浸润巨噬细胞活化中的作用，通过用T细胞特异性抗体处理小鼠从动脉移植物中耗尽T细胞，并监测单核因子的产生。为了证明T细胞在植入物中扩增的疾病相关性，从组织段分离T细胞并过继转移到植入有同系动脉的小鼠中。原位生产的淋巴因子，然后determined.Results：穿透动脉壁的所有层的炎性浸润持续在异种移植，表明炎性病灶代表独立的功能单位。在新鲜和移植组织中检测到类似数量的T细胞和巨噬细胞源性细胞因子。然而，植入后组织浸润T细胞的多样性下降。具有相同T细胞受体的T细胞在植入同一患者组织碎片的不同小鼠中扩增，这表明动脉壁中的T细胞存活是一个非随机过程。为了确认这些T细胞的疾病相关性，进行了T细胞耗尽和重建实验。抗体介导的T细胞从异种移植物中的消除导致单核因子IL-1 β和IL-6的产生减弱。同基因组织来源的T细胞，但不是外周血T细胞，移植到SCID小鼠增强IL-2和IFN-γ的转录在植入arteries.Conclusions：GCA的血管病变维持在人类动脉小鼠嵌合体，表明所有必要的疾病的细胞和非细胞成分都存在于颞动脉。组织浸润性T细胞和巨噬细胞的活化依赖于在异种移植物中具有存活优势的罕见的病变T细胞亚群。这些T细胞在动脉中的选择性增殖表明存在对局部表达的抗原的识别。因此，这些T细胞应该成为GCA新治疗策略的候选靶点。
Background: Giant cell arteritis (GCA) is a systemic vasculitis that preferentially targets medium-sized and large arteries. The etiopathogenesis of the syndrome is not known, and because of the paucity of information concerning the mechanisms of blood vessel wall damage, treatment options are limited. Clues to pathogenic events in this arteritis may derive from understanding the function of tissue-infiltrating cells. Arterial injury in GCA is associated with the formation of granulomas that are composed of T cells, activated macrophages, and multinucleated giant cells. To examine the role of T cells, we implanted inflamed temporal arteries from patients with GCA into severe combined immunodeficiency (SCID) mice and studied whether the vascular lesions were T cell-dependent.Materials and Methods: Temporal artery specimens from patients with GCA were engrafted into SCID mice. The histomorphologic appearance of fresh arteries and grafts retrieved from the mice was compared by two-color immunohistochemistry, and the functional profile of tissue-infiltrating cells was analyzed by semiquantifying cytokine transcription with a polymerase chain reaction (PCR)-based assay system. The repertoire of tissue-infiltrating T cells was assessed for the presence of dominant T cell populations by using T cell receptor beta-chain-specific PCR followed by sequencing. To investigate the role of T cells in the activation of tissue-infiltrating macrophages, T cells were depleted from the arterial grafts by treating the mice with T cell-specific antibodies and the production of monokines was monitored. To demonstrate the disease relevance of T cells expanding in the implants, T cells were isolated from tissue segments and adoptively transferred into mice implanted with syngeneic arteries. The in situ production of lymphokines was then determined.Results: The inflammatory infiltrate penetrating all layers of the arterial wall persisted in the xenotransplants, indicating that the inflammatory foci represent independent functional units. Similar quantities of T cell-and macrophage-derived cytokines were detected in fresh and engrafted tissue. However, the diversity of tissue-infiltrating T cells deceased following implantation. T cells with identical T cell receptors were expanded in different mice that had been engrafted with tissue fragments from the same patient, indicating that T cell survival in the arterial wall was a nonrandom process. To confirm the disease relevance of these T cells, T cell depletion and reconstitution experiments were performed. Antibody-mediated elimination of T cells from the xenotransplants resulted in the attenuation of the production of the monokines, IL-1 beta and IL-6. Adoptive transfer of syngeneic tissue-derived T cells, but not of peripheral blood T cells, into engrafted SCID mice enhanced the transcription of IL-2 and IFN-gamma in the implanted arteries.Conclusions: The vascular lesions of GCA are maintained in human artery-mouse chimeras, indicating that all cellular and noncellular components necessary for the disease are present in the temporal artery. Activation of tissue-infiltrating T cells and macrophages depends upon an infrequent subpopulation of lesional T cells that have a survival advantage in the xenotransplants. The selective proliferation of these T cells in the arteries suggests that there is recognition of a locally expressed antigen. Therefore, these T cells should be candidate targets for the development of novel therapeutic strategies in GCA.