Experimental Renal Transplantation, Laboratory of Experimental Nephrology, IDIBELL. Hospital Universitari de Bellvitge, Laboratori 4122, 4a Pl. Pavelló Govern, Campus Bellvitge, Barcelona, Spain.
Gene Ther. 2011 Oct;18(10):945-52. doi: 10.1038/gt.2011.39. Epub 2011 Apr 7.
The humoral branch of the immune response has an important role in acute and chronic allograft dysfunction. The CD40/CD40L costimulatory pathway is crucial in B- and T- alloresponse. Our group has developed a new small interfering RNA (siRNA) molecule against CD40 that effectively inhibits its expression. The aim of the present study was to prevent rejection in an acute vascular rejection model of kidney transplant by intra-graft gene silencing with anti-CD40 siRNA (siCD40), associated or not with sub-therapeutic rapamycin. Four groups were designed: unspecific siRNA as control; sub-therapeutic rapamycin; siCD40; and combination therapy. Long-surviving rats were found only in both siCD40-treated groups. The CD40 mRNA was overexpressed in control grafts but treatment with siCD40 decreased its expression. Recipient spleen CD40+ B-lymphocytes were reduced in both siCD40-treated groups. Moreover, CD40 silencing reduced donor-specific antibodies, graft complement deposition and immune-inflammatory mediators. The characteristic histological features of humoral rejection were not found in siCD40-treated grafts, which showed a more cellular histological pattern. Therefore, the intra-renal effective blockade of the CD40/CD40L signal reduces the graft inflammation as well as the incidence of humoral vascular acute rejection, finally changing the type of rejection from humoral to cellular.
体液免疫反应在急性和慢性同种异体移植物功能障碍中具有重要作用。CD40/CD40L 共刺激途径在 B 和 T 同种异体反应中至关重要。我们的研究小组开发了一种针对 CD40 的新型小干扰 RNA（siRNA）分子，可有效抑制其表达。本研究旨在通过抗 CD40 siRNA（siCD40）进行移植肾内基因沉默，来预防急性血管排斥反应模型中的排斥反应，同时联合或不联合亚治疗剂量雷帕霉素。设计了四个组：非特异性 siRNA 作为对照；亚治疗剂量雷帕霉素；siCD40；和联合治疗。只有在接受 siCD40 治疗的两组中发现了长期存活的大鼠。在对照组移植物中 CD40 mRNA 过表达，但 siCD40 治疗降低了其表达。在接受 siCD40 治疗的两组中，受体脾 CD40+B 淋巴细胞减少。此外，CD40 沉默减少了供体特异性抗体、移植物补体沉积和免疫炎症介质。在接受 siCD40 治疗的移植物中未发现体液排斥的特征性组织学特征，其表现出更具细胞性的组织学模式。因此，肾内 CD40/CD40L 信号的有效阻断减少了移植物炎症以及体液性急性血管排斥反应的发生，最终将排斥反应的类型从体液性转变为细胞性。
