Qi F, Adair A, Ferenbach D, Vass D G, Mylonas K J, Kipari T, Clay M, Kluth D C, Hughes J, Marson L P
Phagocyte Laboratory, Centre for Inflammation Research, Queen's Medical Research Institute, Little France Crescent, Edinburgh EH16 4TJ, United Kingdom.
Transplantation. 2008 Nov 15;86(9):1267-74. doi: 10.1097/TP.0b013e318188d433.
Acute rejection increases the risk of late renal allograft loss with tubular atrophy, interstitial fibrosis, and microvascular rarefaction. Evidence supports a role for macrophages in promoting allograft injury, but the pathogenic mechanisms are unclear. Using a model of acute rejection, we sought evidence of macrophage-mediated endothelial cell cytotoxicity leading to loss of the renal microvasculature.
We used a transgenic conditional ablation strategy to deplete circulating monocytes and infiltrating renal macrophages after kidney transplantation. CD11b-DTR mice (FVB/nj strain) are transgenic for the human diphtheria toxin receptor gene under the control of the CD11b promoter. Administration of diphtheria toxin results in rapid ablation of circulating monocytes and resident/infiltrating renal macrophages. Transplants were performed between fully mismatched strains (Balb/c donor into control nontransgenic FVB/nj recipient; allograft group), between FVB/nj littermates (isograft group), and from Balb/c donors into CD11b-DTR mice (DT-treated group). Diphtheria toxin was administered at days 3 and 5, and the effect of monocyte/macrophage depletion on changes in renal microvasculature was determined at day 7.
Conditional monocyte and macrophage ablation effectively depleted infiltrating macrophages in murine renal allografts at day 7. Macrophage ablation reduced histologic features of rejection (arteritis, tubulitis) and the accompanying rarefaction of peritubular capillaries at 7 days. The identification of macrophages immunopositive for inducible nitric oxide synthase implicated nitric oxide generation as a possible mechanism of endothelial cell cytotoxicity.
These data indicate a significant role for macrophages in causing acute rejection-related tissue injury that is, at least in part, targeted to the microcirculation.
急性排斥反应会增加肾移植后期移植物丢失的风险，伴有肾小管萎缩、间质纤维化和微血管稀疏。有证据支持巨噬细胞在促进移植物损伤中起作用，但致病机制尚不清楚。我们利用急性排斥反应模型，寻找巨噬细胞介导的内皮细胞细胞毒性导致肾微血管丢失的证据。
我们采用转基因条件性消融策略，在肾移植后清除循环单核细胞和浸润性肾巨噬细胞。CD11b-DTR小鼠（FVB/nj品系）是在CD11b启动子控制下的人白喉毒素受体基因的转基因小鼠。给予白喉毒素可迅速清除循环单核细胞和驻留/浸润性肾巨噬细胞。在完全不匹配的品系之间进行移植（Balb/c供体到对照非转基因FVB/nj受体；同种异体移植组）、FVB/nj同窝小鼠之间（同基因移植组）以及从Balb/c供体到CD11b-DTR小鼠（DT处理组）。在第3天和第5天给予白喉毒素，并在第7天确定单核细胞/巨噬细胞清除对肾微血管变化的影响。
条件性单核细胞和巨噬细胞消融在第7天有效清除了小鼠肾同种异体移植物中的浸润性巨噬细胞。巨噬细胞消融减少了第7天排斥反应的组织学特征（动脉炎、肾小管炎）以及伴随的肾小管周围毛细血管稀疏。诱导型一氧化氮合酶免疫阳性的巨噬细胞的鉴定表明一氧化氮生成可能是内皮细胞细胞毒性的一种机制。
这些数据表明巨噬细胞在引起急性排斥反应相关组织损伤中起重要作用，这种损伤至少部分针对微循环。
