Abstract：
Inflammatory monocytes are a major component of the cellular infiltrate in acutely rejecting human kidney allografts. Since immune-modifying nanoparticles (IMPs) bind to circulating inflammatory monocytes via the specific scavenger receptor MARCO, causing diversion to the spleen and subsequent apoptosis, we investigated the therapeutic potential of negatively charged, 500-nm diameter polystyrene IMPs to prevent kidney allograft rejection. Kidney transplants were performed from BALB/c (H2d) to C57BL/6 (H2b) mice in two groups: controls (allo) and allo mice infused with IMPs. Groups were studied for 14 (acute rejection) or 100 (chronic rejection) days. Allo mice receiving IMPs exhibited superior survival and markedly less acute rejection, with better kidney function, less tubulitis, and diminished inflammatory cell density, cytokine and cytotoxic molecule expression in the allograft and lower titers of donor-specific IgG2c antibody in serum at day 14, as compared to allo mice. Cells isolated from kidneys from allo mice receiving IMPs showed reduced Ly6Chi monocytes, CD11b+ cells and NKT+ cells compared to allo mice. IMPs predominantly bound CD11b+ cells in the bloodstream and CD11b+ and CD11c-B220+ marginal zone B cells in the spleen. In the spleen, IMPs were found predominantly in red pulp, colocalized with MARCO and expression of cleaved caspase-3. At day 100, allo mice receiving IMPs exhibited reduced macrophage M1 responses but were not protected from chronic rejection. IMPs afforded significant protection from acute rejection, inhibiting both innate and adaptive alloimmunity. Thus, our current experimental findings, coupled with our earlier demonstration of IMP-induced protection in kidney ischemia-reperfusion injury, identify IMPs as a potential induction agent in kidney transplantation.
摘要：
炎性单核细胞是急性排斥人肾脏同种异体移植物中细胞浸润的主要成分。由于免疫修饰纳米颗粒（IMP）通过特异性清道夫受体MARCO与循环炎性单核细胞结合，导致转移到脾脏和随后的细胞凋亡，我们研究了带负电荷的治疗潜力，500纳米直径的聚苯乙烯IMP，以防止肾脏同种异体移植排斥。从BALB/c(H2d)向C57BL/6(H2b)小鼠进行肾脏移植,分为两组:对照(allo)和输注IMP的allo小鼠。研究组14（急性排斥）或100（慢性排斥）天。接受IMP的同种异体小鼠表现出优越的存活率和明显较少急性排斥反应，有更好的肾功能，少了根瘤炎,炎症细胞密度降低，与同种异体小鼠相比，同种异体移植物中的细胞因子和细胞毒性分子表达以及第14天血清中供体特异性IgG2c抗体的滴度较低。从接受IMPs的allo小鼠的肾脏中分离的细胞显示出减少的Ly6Chi单核细胞，CD11b+细胞和NKT+细胞与同种异体小鼠比较。IMP主要结合血流中的CD11b+细胞和脾脏中的CD11b+和CD11c-B220+边缘区B细胞。在脾脏里,IMP主要在红色纸浆中发现，与MARCO共定位并表达裂解的caspase-3。在第100天,接受IMP的同种异体小鼠表现出降低的巨噬细胞M1应答,但未被保护免于慢性排斥。IMP对急性排斥反应有显著的保护作用，抑制先天和适应性同种免疫。因此，我们目前的实验发现，再加上我们早期证明IMP在肾脏缺血再灌注损伤中的保护作用，确定IMP是肾移植的潜在诱导剂。
