Elevation of high-mobility group box 1 after clinical autologous islet transplantation and its inverse correlation with outcomes.
Elevation of high-mobility group box 1 after clinical autologous islet transplantation and its inverse correlation with outcomes.
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DOI：
10.3727/096368912x658980
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发表时间：
2014-02
影响因子：
3.3
通讯作者：
Matsumoto S
中科院分区：
文献类型：
--
作者：
Itoh T;Iwahashi S;Kanak MA;Shimoda M;Takita M;Chujo D;Tamura Y;Rahman AM;Chung WY;Onaca N;Coates PT;Dennison AR;Naziruddin B;Levy MF;Matsumoto S
临床自体胰岛移植（AIT）后的一个主要问题是难以实现胰岛素非依赖性。为了跟进我们在小鼠模型中证明的高迁移率族蛋白1（HMGB 1）从胰岛中释放并参与移植胰岛的早期丢失，我们测试了HMGB 1在临床AIT中的作用。15例AIT患者的血清HMGB 1水平在胰岛输注期间（7.6 ± 1.2 ng/ml）和输注后24 h（8.0 ± 1.4 ng/ml）显著高于入院水平（2.4 ± 0.6 ng/ml）。HMGB 1的首次升高与胰岛损伤有关，但随后的升高与胰岛损伤无关。AIT组HMGB 1水平从入院到第一个峰值的变化（Δ HMGB 1）（8.1 ± 1.1 ng/ml）显著高于单纯胰腺切除对照组（2.2 ± 0.5 ng/ml）（p < 0.05）。循环血清可溶性晚期糖基化终产物受体（sCRP）水平也在胰岛输注期间升高。体外研究表明，受损的人胰岛释放HMGB 1，但不释放sIgA。在结局方面，无胰岛素组的Δ HMGB 1（5.2 ± 0.6 ng/ml）显著低于胰岛素依赖组（分别为10.6 ± 1.9 ng/ml和0.7 ± 0.2 ng/ml），而Δ SHB 1（2.3 ± 0.6 ng/ml）显著高于胰岛素依赖组（分别为10.6 ± 1.9 ng/ml和0.7 ± 0.2 ng/ml）。Δ HMGB 1与白色细胞数、IP-10、EGF和eotaxin相关。总之，AIT患者血清HMGB 1水平升高，可能与炎症反应有关，而炎症反应会使胰岛植入恶化。因此，抗HMGB 1治疗可能是进一步改善临床AIT结局的候选药物。
A major problem after clinical autologous islet transplantation (AIT) is the difficulty in achieving insulin independence. To follow up on our demonstration in a murine model that high-mobility group box 1 (HMGB1) was released from islets and involved in early loss of transplanted islets, we tested the role of HMGB1 in clinical AIT. Serum HMGB1 levels from 15 AIT patients were significantly elevated during islet infusion (7.6 ± 1.2 ng/ml) and 24 h after infusion (8.0 ± 1.4 ng/ml) compared to admission levels (2.4 ± 0.6 ng/ml). The first elevation of HMGB1 was associated with islet damage, but the later elevation was not. The change in the HMGB1 level from admission to first peak (ΔHMGB1) was significantly higher in the AIT group (8.1 ± 1.1 ng/ml) than in the pancreatectomy-only control (2.2 ± 0.5 ng/ml) (p < 0.05). Circulating serum levels of soluble receptor for advanced glycation end products (sRAGE) were also elevated during islet infusion. In vitro studies demonstrated that damaged human islets released HMGB1 but not sRAGE. In terms of outcomes, the insulin-free group showed significantly lower ΔHMGB1 (5.2 ± 0.6 ng/ml) and higher ΔsRAGE (2.3 ± 0.6 ng/ml) than the insulin-dependent group (10.6 ± 1.9 ng/ml and 0.7 ± 0.2 ng/ml, respectively). The ΔHMGB1 correlated with the number of white blood cell, IP-10, EGF, and eotaxin. In conclusion, serum HMGB1 was elevated in AIT and could be associated with inflammatory reactions that deteriorate islet engraftment. Therefore, anti-HMGB1 therapy might be a candidate for further improving the outcomes of clinical AIT.