Department of General and Transplantation Surgery, Warsaw Medical University, Warsaw, Poland.
PLoS One. 2009 Dec 2;4(12):e8020. doi: 10.1371/journal.pone.0008020.
The allochimeric MHC class I molecule [alpha1h1/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.
METHODOLOGY/PRINCIPAL FINDINGS: 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.
含有供体型（WF；RT1u）表位的同种异体 MHC Ⅰ类分子 [alpha1h1/u]-RT1.Aa，与亚治疗剂量环孢素（CsA）联合给药，可在大鼠模型中诱导同种异体心脏移植物的无限期存活。在血管化移植模型中，脾脏通过产生同种抗原反应性 T 细胞来促进移植物排斥。同种异体移植物排斥中的免疫反应涉及一系列分子事件，导致 T 细胞与抗原呈递细胞之间形成免疫突触。
方法/主要发现：为了阐明同种异体分子的免疫抑制功能所涉及的分子途径，我们对未处理、CsA 处理和同种异体分子+亚治疗剂量 CsA 处理的动物的脾脏 T 细胞进行了微阵列和定量 RT-PCR 分析，在移植后第 1、3 和 7 天。同种异体分子处理导致参与肌动蛋白丝聚合（RhoA 和 Rac1）、细胞黏附（Catna1、Vcam 和 CD9）、液泡运输（RhoB、Cln8 和 ATP6v1b2）和 MAPK 途径（Spred1 和 Dusp6）的基因下调，这些基因参与微管细胞骨架的重排和肌动蛋白与微管细胞骨架之间的相互作用。所有这些基因都参与 T 细胞极性和运动性，即它们移动、扫描和与抗原呈递细胞（APCs）形成功能性免疫突触的能力。
这些结果表明，同种异体分子的免疫抑制功能可能取决于 T 细胞运动和扫描能力的受损，并且可能还取决于免疫突触的形成。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。
