Terness Peter, Oelert Thilo, Ehser Sandra, Chuang Jing Jing, Lahdou Imad, Kleist Christian, Velten Florian, Hämmerling Günter J, Arnold Bernd, Opelz Gerhard
Institute of Immunology, Department of Transplantation Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18442-7. doi: 10.1073/pnas.0807185105. Epub 2008 Nov 18.
Treatment of autoimmune diseases remains a challenge for immunological research. An ideal therapy should inhibit the immune reaction against the diseased organ and leave the rest of the immune response intact. Our previous studies showed that donor-derived dendritic cells (DCs) treated in vitro with mitomycin C (MMC) suppress rat heart allograft rejection if injected into recipients before transplantation. Here we analyze their efficacy in controlling autoimmunity. MMC-DCs loaded with myelin-basic-protein (MBP) inhibited specific T cells derived from multiple sclerosis patients in vitro. If coincubated with MMC-DCs, T cells were arrested in the G(0)/G(1) cell cycle phase. Microarray gene scan showed that MMC influences the expression of 116 genes in DCs, one main cluster comprising apoptotic and the second cluster immunosuppressive genes. Apparently, the combination of apoptosis with expression of tolerogenic molecules renders MMC-DCs suppressive. MBP-loaded MMC-DCs also inhibited mouse T cells in vitro and, in contrast to MBP-loaded naïve DCs, did not induce experimental autoimmune encephalitis. Most importantly, mice vaccinated with inhibitory DCs became resistant to the disease. Whereas this is not the first report on generation of suppressive DCs, it delineates a method using a clinically approved drug at nontoxic concentrations, which yields irreversibly changed DCs, effective across species in vitro and in vivo.
自身免疫性疾病的治疗仍然是免疫学研究面临的一项挑战。理想的治疗方法应抑制针对患病器官的免疫反应，同时保持其余免疫反应完好无损。我们之前的研究表明，体外经丝裂霉素C（MMC）处理的供体来源树突状细胞（DC），若在移植前注入受体，可抑制大鼠心脏同种异体移植排斥反应。在此，我们分析它们在控制自身免疫方面的功效。负载髓鞘碱性蛋白（MBP）的MMC-DC在体外可抑制来自多发性硬化症患者的特异性T细胞。若与MMC-DC共同孵育，T细胞会停滞在G(0)/G(1)细胞周期阶段。基因芯片扫描显示，MMC会影响DC中116个基因的表达，一个主要簇包含凋亡相关基因，另一个簇包含免疫抑制基因。显然，凋亡与耐受性分子表达的结合使MMC-DC具有抑制作用。负载MBP的MMC-DC在体外也能抑制小鼠T细胞，并且与负载MBP的未成熟DC不同，不会诱发实验性自身免疫性脑脊髓炎。最重要的是，用抑制性DC接种的小鼠对该疾病产生了抗性。虽然这并非关于产生抑制性DC的首篇报道，但它描述了一种使用临床批准药物、无毒浓度的方法，该方法能产生不可逆改变的DC，在体外和体内对不同物种均有效。
