Guillonneau Carole, Louvet Cédric, Renaudin Karine, Heslan Jean-Marie, Heslan Michèle, Tesson Laurent, Vignes Caroline, Guillot Cécile, Choi Yongwon, Turka Lawrence A, Cuturi Maria-Cristina, Anegon Ignacio, Josien Régis
Institut National de la Santé et de la Recherche Médicale Unit 437, and Institut de Transplantation et de Recherche en Transplantation, Nantes, France.
J Immunol. 2004 Feb 1;172(3):1619-29. doi: 10.4049/jimmunol.172.3.1619.
We analyzed the role of TNF-related activation-induced cytokine (TRANCE), a member of the TNF family expressed on activated T cells that shares functional properties with CD40L, and its receptor-activating NF-kappaB (RANK) which is mostly expressed on mature dendritic cells, during allogenic responses in vivo using a rodent heart allograft model. TRANCE mRNA was strongly up-regulated in acutely rejected allografts on days 4 and 5 posttransplantation whereas RANK was detected as early as day 1 but did not show further up-regulation during the first week. Immunofluoresence analyses of heart allografts showed that 80 and 100% of TRANCE and RANK-expressing cells were T cells and APCs, respectively. We show for the first time that short-term TRANCE blockade using a mouse RANKIg fusion molecule can significantly prolong heart allograft survival in both rat and mouse models. Similarly, rat heart allografts transduced with a RANKIg encoding recombinant adenovirus exhibited a significant prolongation of survival (14.3 vs 7.6 days, p < 0.0001). However, TRANCE blockade using RANKIg did not appear to inhibit allogeneic T and B cell priming humoral responses against RANKIg. Interestingly, TRANCE blockade induced strong up-regulation of CD40 ligand (CD40L) mRNA in allografts. Combined CD40L and TRANCE blockade resulted in significantly decreased chronic allograft rejection lesions as well as allogeneic humoral responses compared with CD40L blockade alone. We conclude that TRANCE-RANK interactions play an important role during acute allograft rejection and that CD40L-independent allogeneic immune responses can be, at least in part, dependent on the TRANCE pathway of costimulation.
我们使用啮齿动物心脏移植模型，分析了肿瘤坏死因子相关激活诱导细胞因子（TRANCE）及其受体激活核因子κB（RANK）在体内同种异体反应中的作用。TRANCE是肿瘤坏死因子家族的成员，在活化的T细胞上表达，与CD40L具有共同的功能特性；RANK主要在成熟树突状细胞上表达。移植后第4天和第5天，急性排斥的同种异体移植物中TRANCE mRNA强烈上调，而RANK早在第1天就被检测到，但在第一周内未进一步上调。心脏同种异体移植物的免疫荧光分析表明，表达TRANCE和RANK的细胞中，分别有80%和100%是T细胞和抗原呈递细胞（APC）。我们首次表明，使用小鼠RANKIg融合分子短期阻断TRANCE，可在大鼠和小鼠模型中显著延长心脏同种异体移植物的存活时间。同样，用编码RANKIg的重组腺病毒转导的大鼠心脏同种异体移植物，其存活时间也显著延长（14.3天对7.6天，p<0.0001）。然而，使用RANKIg阻断TRANCE似乎并未抑制同种异体T细胞和B细胞针对RANKIg的初次体液反应。有趣的是，阻断TRANCE可诱导同种异体移植物中CD40配体（CD40L）mRNA的强烈上调。与单独阻断CD40L相比，联合阻断CD40L和TRANCE可显著减少慢性同种异体移植排斥病变以及同种异体体液反应。我们得出结论，TRANCE-RANK相互作用在急性同种异体移植排斥中起重要作用，并且不依赖CD40L的同种异体免疫反应至少部分依赖于TRANCE共刺激途径。
