Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system
Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system
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通过使用新型多糖 siRNA 递送系统，永久接受带有 CD40 siRNA 的小鼠同种异体心脏移植物以诱导调节性骨髓细胞
DOI：
10.1038/gt.2014.119
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发表时间：
2015
期刊：
影响因子：
5.1
通讯作者：
Li Xiao K*. Takahara S
中科院分区：
文献类型：
--
作者：
Zhang Q;Ichimaru N;Higuchi S;Cai SJ;Hou JG;Fujino M;Nonomura N;Kobayashi M;Ando H;Uno A;Sakurai K;Mochizuki S;Adachi Y;Ohno N;Zou HJ;Xu JH;Li Xiao K*. Takahara S
CD 40/CD 154共刺激通路在同种免疫应答中至关重要。我们开发了一种新型的小干扰RNA（siRNA）递送系统，其在siRNA正义链的5′-末端具有poly-dA延伸，该poly-dA延伸稳定地掺入1，3-β-葡聚糖（SPG）中。这被捕获并通过其受体Dectin-1掺入树突状细胞（DC）中，特异性沉默CD 40基因（siCD 40）以发挥免疫调节活性。siCD 40/SPG处理的CBA小鼠永久接受B10完全不匹配的心脏同种异体移植物。与移植物存活一致，移植物中的CD 4+、CD 8 + T细胞浸润较低，并且移植物和受体脾中的CD 40低CD 11 c + DC细胞和CD 4 + Foxp 3+细胞的数量增加。此外，给予来自具有siCD 40/SPG的原代受体的脾细胞过继转移的幼稚CBA受体接受来自供体型B10的心脏移植物，而不是第三方Balb/c小鼠。总之，用siCD 40/SPG靶向DC治疗可以产生抗原特异性TcR，导致小鼠心脏同种异体移植物的永久接受。这些发现对于阐明DCs诱导耐受的机制具有重要意义，也突出了免疫调节的潜力和基于siRNA的临床治疗在移植领域的可行性。
The CD40/CD154 co-stimulatory pathway is crucial in alloimmune response. We developed a novel small interfering RNA (siRNA) delivery system with a poly-dA extension at the 5′-end of the siRNA sense strand that was stably incorporated into 1, 3-β-glucan (schizophyllan, SPG). This was captured and incorporated into dendritic cells (DCs) through its receptor, Dectin-1, specifically silencing CD40 genes (siCD40) to exert immunoregulatory activity. siCD40/SPG-treated CBA mice permanently accepted B10 fully mismatched cardiac allografts. Consistent with graft survival, the infiltration of CD4+, CD8+ T cells into the graft was lower, and that the numbers of CD40 low CD11c+ DCs cells and CD4+ Foxp3+ cells were increased in both the graft and in the recipient spleen. In addition, naive CBA recipients given an adoptive transfer of splenocytes from the primary recipients with siCD40/SPG accepted a heart graft from donor-type B10, but not third-party Balb/c mice. In conclusion, the treatment with siCD40/SPG targeting DCs could generate antigen-specific Tregs, resulting in the permanent acceptance of mouse cardiac allografts. These findings have important implications for clarifying the mechanism underlying the induction of tolerance in DCs, and also highlight the potential of immunomodulation and the feasibility of siRNA-based clinical therapy in the transplantation field.