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 (H2^d) to C57BL/6 (H2^b) 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 Ly6C^hi 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.

炎性单核细胞是急性排斥人类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 与循环炎症单核细胞结合，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 500 nm 直径聚苯乙烯IMP 预防肾脏同种异体移植排斥反应的治疗潜力。肾脏移植从 BALB/c (H2^d) 到 C57BL/6 (H2^b) 小鼠分为两组：对照组 (allo) 和 allo注射了 IMP 的小鼠。对各组进行 14 天（急性排斥）或 100 天（慢性排斥）研究。接受 IMP 的同种异体小鼠表现出更高的存活率和明显更少的急性排斥反应，肾功能更好，肾小管炎更少，同种异体移植物中的炎症细胞密度、细胞因子和细胞毒性分子表达减少，第 14 天时血清中供体特异性 IgG2c 抗体的滴度更低，与同种异体小鼠相比。与同种异体小鼠相比，从接受 IMP 的同种异体小鼠的肾脏中分离出的细胞显示 Ly6C ^hi单核细胞、CD11b⁺细胞和 NKT⁺细胞减少。IMPs 主要结合血流中的 CD11b⁺细胞以及 CD11b⁺和 CD11c-B220⁺脾脏边缘区 B 细胞。在脾脏中，IMPs 主要存在于红髓中，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减少的巨噬细胞 M1 反应，但未受到慢性排斥反应的保护。IMPs 对急性排斥提供了显着的保护，抑制了先天性和适应性同种异体免疫。因此，我们目前的实验结果，加上我们早先对 IMP 诱导的肾缺血再灌注损伤保护作用的证明，将 IMP 确定为肾移植中的潜在诱导剂。