Background

Despite significant advances in transplantation, acute cellular rejection (AR) remains a major obstacle that is most prevalent in the first months post heart transplantation (HT). Current treatments require high doses of immunosuppressive drugs followed by maintenance therapies that have systemic side effects including early infection. In this study, we attempted to prevent AR with a myocardial-targeted galectin-7-siRNA delivery method using cationic microbubbles (CMBs) combined with ultrasound targeted microbubble destruction (UTMD) to create local immunosuppression in a rat abdominal heterotopic heart transplantation acute rejection model.

Methods and results

Galectin-7-siRNA (siGal-7) bound to CMBs were synthesized and effective ultrasound-targeted delivery of siGal-7 into target cells confirmed in vitro. Based on these observations, three transplant rat models were tested：①isograft (ISO); ② Allograft (ALLO) +UTMD; and ③ALLO + PBS. UTMD treatments were administered at 1, 3, 5, 7 days after HT. Galectin 7 expression was reduced by 50% compared to ALLO + PBS (p < 0.005), and this was associated with significant reductions in both galectin 7 and Interleukin-2 protein levels (p < 0.001). The ALLO + UTMD group had Grade II or less inflammatory infiltration and myocyte damage in 11/12 rats using International Society For Heart and Lung Transplantation grading, compared to 0/12 rats with this grading in the ALLO + PBS group at 10 days post HT (p < 0.001).

Conclusions

Ultrasound-targeted galectin-7-siRNA knockdown with UTMD can prevent acute cellular rejection in the early period after allograft heart transplantation without the need for systemic immunosuppression.

Key words

Microbubble, Acute Rejection, Heart Transplantation, Galectin-7, RNA.

中文翻译：

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在啮齿类动物模型中，用超声微泡靶向基因治疗作为靶向治疗的靶向半乳凝素7抑制是防止心脏移植后急性排斥反应的唯一疗法。

背景

尽管移植取得了重大进展，但是急性细胞排斥反应（AR）仍然是主要的障碍，在心脏移植（HT）后的最初几个月中最为普遍。当前的治疗需要高剂量的免疫抑制药物，然后是具有全身副作用（包括早期感染）的维持疗法。在这项研究中，我们试图通过使用心肌微泡（CMBs）和超声微泡破坏（UTMD）结合的心肌靶向半乳糖凝集素7-siRNA递送方法预防AR，以在大鼠腹部异位心脏移植急性排斥模型中产生局部免疫抑制作用。

方法与结果

合成了结合CMB的Galectin-7-siRNA（siGal-7），并在体外确认了将siGal-7超声靶向递送到靶细胞的有效方法。基于这些观察结果，测试了三种移植大鼠模型：①同种异体移植（ISO）；②同种异体移植物（ALLO）+ UTMD; ③ALLO+ PBS。HT后1、3、5、7天给予UTMD治疗。与ALLO + PBS相比，galectin 7的表达降低了50％（p  <0.005），这与galectin 7和Interleukin-2蛋白水平的显着降低有关（p  <0.001）。采用国际心脏和肺移植协会分级的ALLO + UTMD组在11/12只大鼠中有II级或以下的炎症浸润和心肌细胞损伤，相比于HT后10天的ALLO + PBS组中的0/12只大鼠具有II级或更低的炎症浸润和心肌细胞损伤（p  <0.001）。

结论

用UTMD进行超声靶向的galectin-7-siRNA敲低可以防止同种异体心脏移植术后早期的急性细胞排斥反应，而无需进行全身性免疫抑制。

关键词

微泡，急性排斥，心脏移植，半乳凝素7，RNA。