Down regulation of genes involved in T cell polarity and motility during the induction of heart allograft tolerance by allochimeric MHC I.
Down regulation of genes involved in T cell polarity and motility during the induction of heart allograft tolerance by allochimeric MHC I.
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DOI：
10.1371/journal.pone.0008020
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发表时间：
2009-12-02
期刊：
影响因子：
3.7
通讯作者：
Ghobrial RM
中科院分区：
文献类型：
--
作者：
Lisik W;Tejpal N;Gong Y;Skelton TS;Ganachari M;Bremer EG;Kloc M;Ghobrial RM
异源嵌合 MHC I 类分子 [α1h1/u]-RT1.Aa 含有供体型（Wistar Furth，WF；RT1u）表位，显示在受体型（ACI，RT1a）上，与亚治疗剂量的环孢菌素（CsA）联合给药，可诱导大鼠模型中异位心脏同种异体移植物的无限期存活。在血管化移植模型中，脾脏通过产生同种异体抗原反应性 T 细胞来促进移植物排斥。同种异体移植排斥中的免疫反应涉及一系列分子事件，导致 T 细胞和抗原呈递细胞之间形成免疫突触。为了阐明异源嵌合分子免疫抑制功能中涉及的分子途径，我们对移植后第 1、3 和 7 天的未处理、CsA 处理和异源嵌合分子 + 亚治疗剂量的 CsA 处理动物的脾 T 细胞的基因表达谱进行了微阵列和定量 RTPCR 分析。同种异体嵌合分子处理导致参与肌动蛋白丝聚合（RhoA和Rac1）、细胞粘附（Catna1、Vcam和CD9）、液泡运输（RhoB、Cln8和ATP6v1b2）以及参与微管蛋白细胞骨架重组和肌动蛋白与微管细胞骨架之间相互作用的MAPK途径（Spred1和Dusp6）的基因下调。所有这些基因都涉及 T 细胞极性和运动性，即它们移动、扫描以及与抗原呈递细胞 (APC) 形成功能性免疫突触的能力。这些结果表明，异源嵌合分子的免疫抑制功能可能依赖于T细胞运动和扫描能力的受损，也可能依赖于免疫突触的形成。我们相信这些新发现可能对器官移植具有重要的临床意义。
The allochimeric MHC class I molecule [α1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) epitopes displayed on recipient-type (ACI, RT1a) administered in conjunction with sub-therapeutic dose of cyclosporine (CsA) induces indefinite survival of heterotopic cardiac allografts in rat model. In vascularized transplantation models, the spleen contributes to graft rejection by generating alloantigen reactive T cells. The immune response in allograft rejection involves a cascade of molecular events leading to the formation of immunological synapses between T cells and the antigen-presenting cells. To elucidate the molecular pathways involved in the immunosuppressive function of allochimeric molecule we performed microarray and quantitative RTPCR analyses of gene expression profile of splenic T cells from untreated, CsA treated, and allochimeric molecule + subtherapeutic dose of CsA treated animals at day 1, 3 and 7 of post transplantation. Allochimeric molecule treatment caused down regulation of genes involved in actin filament polymerization (RhoA and Rac1), cell adhesion (Catna1, Vcam and CD9), vacuolar transport (RhoB, Cln8 and ATP6v1b2), and MAPK pathway (Spred1 and Dusp6) involved in tubulin cytoskeleton reorganization and interaction between actin and microtubule cytoskeleton. All these genes are involved in T cell polarity and motility, i.e., their ability to move, scan and to form functional immunological synapse with antigen presenting cells (APCs). These results indicate that the immunosuppressive function of allochimeric molecule may depend on the impairment of T cells' movement and scanning ability, and possibly also the formation of immunological synapse. We believe that these novel findings may have important clinical implications for organ transplantation.
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