Wang Zhiliang, Shufesky William J, Montecalvo Angela, Divito Sherrie J, Larregina Adriana T, Morelli Adrian E
Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
PLoS One. 2009;4(3):e4940. doi: 10.1371/journal.pone.0004940. Epub 2009 Mar 31.
Chronic allograft vasculopathy (CAV) is an atheromatous-like lesion that affects vessels of transplanted organs. It is a component of chronic rejection that conventional immuno-suppression fails to prevent, and is a major cause of graft loss. Indirect allo-recognition through T cells and allo-Abs are critical during CAV pathogenesis. We tested whether the indirect allo-response and its impact on CAV is down-regulated by in situ-delivery of donor Ags to recipient's dendritic cells (DCs) in lymphoid organs in a pro-tolerogenic fashion, through administration of donor splenocytes undergoing early apoptosis. Following systemic injection, donor apoptotic cells were internalized by splenic CD11c(hi) CD8alpha(+) and CD8(-) DCs, but not by CD11c(int) plasmacytoid DCs. Those DCs that phagocytosed apoptotic cells in vivo remained quiescent, resisted ex vivo-maturation, and presented allo-Ag for up to 3 days. Administration of donor apoptotic splenocytes, unlike cells alive, (i) promoted deletion, FoxP3 expression and IL-10 secretion, and decreased IFN-gamma-release in indirect pathway CD4 T cells; and (ii) reduced cross-priming of anti-donor CD8 T cells in vivo. Targeting recipient's DCs with donor apoptotic cells reduced significantly CAV in a fully-mismatched aortic allograft model. The effect was donor specific, dependent on the physical characteristics of the apoptotic cells, and was associated to down-regulation of the indirect type-1 T cell allo-response and secretion of allo-Abs, when compared to recipients treated with donor cells alive or necrotic. Down-regulation of indirect allo-recognition through in situ-delivery of donor-Ag to recipient's quiescent DCs constitutes a promising strategy to prevent/ameliorate indirect allorecognition and CAV.
慢性移植血管病（CAV）是一种影响移植器官血管的动脉粥样硬化样病变。它是慢性排斥反应的一个组成部分，传统免疫抑制无法预防，并且是移植物丢失的主要原因。在CAV发病机制中，通过T细胞和同种异体抗体的间接同种异体识别至关重要。我们测试了通过以促耐受方式向淋巴器官中的受体树突状细胞（DC）原位递送供体抗原，是否能下调间接同种异体反应及其对CAV的影响，方法是给予经历早期凋亡的供体脾细胞。全身注射后，供体凋亡细胞被脾脏CD11c(hi) CD8alpha(+)和CD8(-) DC内化，但未被CD11c(int)浆细胞样DC内化。那些在体内吞噬凋亡细胞的DC保持静止，抵抗体外成熟，并呈递同种异体抗原长达3天。与活细胞不同，给予供体凋亡脾细胞（i）促进间接途径CD4 T细胞的缺失、FoxP3表达和IL-10分泌，并减少IFN-γ释放；（ii）在体内减少抗供体CD8 T细胞的交叉致敏。在完全不匹配的主动脉移植模型中，用供体凋亡细胞靶向受体DC可显著降低CAV。该效应具有供体特异性，取决于凋亡细胞的物理特性，并且与间接1型T细胞同种异体反应的下调和同种异体抗体的分泌相关，与用活的或坏死的供体细胞处理的受体相比。通过向受体静止DC原位递送供体抗原下调间接同种异体识别是预防/改善间接同种异体识别和CAV的一种有前景的策略。
