Heslan Jean Marie, Renaudin Karine, Thebault Pamela, Josien Regis, Cuturi Maria-Cristina, Chiffoleau Elise
Institut National de la Santé et de la Recherche Médicale Unité 643 (INSERM U643) Nantes, France.
Transplantation. 2006 Nov 15;82(9):1185-93. doi: 10.1097/01.tp.0000236573.01428.f3.
Progressively better therapies have largely prevented or at least effectively treated acute allograft rejection. Consequently, the long-term survival of solid organ transplants has increasingly become limited primarily by the development of chronic allograft rejection. The mechanisms of chronic rejection remain largely unknown and the induction of specific tolerance would be the ultimate achievement in transplant immunology. We previously demonstrated, in a fully major histocompatibility complex (MHC)-mismatched rat cardiac allograft combination, that a 20-day treatment with a deoxyspergualin (DSG) analogue, LF15-0195, induces allograft tolerance with the development of potent CD4CD25 regulatory T cells. In order to better characterize the mechanisms involved in allograft tolerance, we compared long-term tolerated allografts with allografts exhibiting signs of chronic rejection induced by donor-specific blood transfusion.
We analyzed both types of allografts for infiltration, alloantibody production and gene expression by histology, exhaustive microarray and quantitative reverse-transcriptase polymerase chain reaction.
Interestingly, we observed in tolerated allografts an infiltrate as dense as the one observed in chronically rejected allografts and alloantibody deposits on graft endothelial cells. Prominent gene expression of many putative proinflammatory cytokines and genes related to cell activation or cytotoxicity were observed in tolerated allografts. However, we observed a specific upregulation of cytoprotective genes such as nitric oxide synthase, BclXL, and indoleamine 2,3 dioxygenase, and a poor in situ expression of immunoglobulin chain gene.
This study demonstrates a state of accommodation of tolerated allografts and suggests the importance of early control of humoral immunity for the prevention of chronic rejection and the maintenance of long-term tolerance.
日益先进的治疗方法在很大程度上预防了急性移植排斥反应，或至少能对其进行有效治疗。因此，实体器官移植的长期存活越来越主要受到慢性移植排斥反应发展的限制。慢性排斥反应的机制在很大程度上仍不明确，而诱导特异性免疫耐受将是移植免疫学的最终目标。我们之前在完全主要组织相容性复合体（MHC）不匹配的大鼠心脏移植组合中证明，用去氧精胍菌素（DSG）类似物LF15 - 0195进行20天的治疗可诱导移植耐受，并产生强效的CD4CD25调节性T细胞。为了更好地描述移植耐受所涉及的机制，我们将长期耐受的移植器官与因供体特异性输血诱导而出现慢性排斥反应迹象的移植器官进行了比较。
我们通过组织学、全基因组芯片和定量逆转录聚合酶链反应分析了这两种类型的移植器官的浸润情况、同种异体抗体产生及基因表达。
有趣的是，我们在耐受的移植器官中观察到与慢性排斥的移植器官中一样密集的浸润以及移植器官内皮细胞上的同种异体抗体沉积。在耐受的移植器官中观察到许多假定的促炎细胞因子以及与细胞活化或细胞毒性相关的基因有显著的基因表达。然而，我们观察到细胞保护基因如一氧化氮合酶、BclXL和吲哚胺2,3 -双加氧酶有特异性上调，且免疫球蛋白链基因的原位表达较差。
本研究证明了耐受移植器官的一种适应状态，并提示早期控制体液免疫对于预防慢性排斥反应和维持长期耐受的重要性。
