Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC, United States.
Massbiologics of the University of Massachusetts Medical School, Boston, MA, United States.
Front Immunol. 2021 Jun 2;12:660900. doi: 10.3389/fimmu.2021.660900. eCollection 2021.
In transplantation, plasmapheresis and IVIg provide the mainstay of treatment directed at reducing or removing circulating donor-specific antibody (DSA), yet both have limitations. We sought to test the efficacy of targeting the IgG recycling mechanism of the neonatal Fc receptor (FcRn) using anti-FcRn mAb therapy in a sensitized non-human primate (NHP) model, as a pharmacological means of lowering DSA.
Six (6) rhesus macaque monkeys, previously sensitized by skin transplantation, received a single dose of 30mg/kg anti-RhFcRn IV, and effects on total IgG, as well as DSA IgG, were measured, in addition to IgM and protective immunity. Subsequently, 60mg/kg IV was given in the setting of kidney transplantation from skin graft donors. Kidney transplant recipients received RhATG, and tacrolimus, MMF, and steroid for maintenance immunosuppression.
Circulating total IgG was reduced from a baseline 100% on D0 to 32.0% (mean, SD ± 10.6) on d4 post infusion (p<0.05), while using a DSA assay. T-cell flow cross match (TFXM) was reduced to 40.6±12.5% of baseline, and B-cell FXCM to 52.2±19.3%. Circulating total IgM and DSA IgM were unaffected by treatment. Pathogen-specific antibodies (anti-gB and anti-tetanus toxin IgG) were significantly reduced for 14d post infusion. Post-transplant, circulating IgG responded to anti-FcRn mAb treatment, but DSA increased rapidly.
Targeting the FcRn-mediated recycling of IgG is an effective means of lowering circulating donor-specific IgG in the sensitized recipient, although in the setting of organ transplantation mechanisms of rapid antibody rise post-transplant remains unaffected.
在移植中，血浆置换和 IVIg 提供了减少或去除循环供体特异性抗体（DSA）的主要治疗方法，但两者都有其局限性。我们试图在致敏的非人类灵长类动物（NHP）模型中测试靶向新生儿 Fc 受体（FcRn）的 IgG 再循环机制的疗效，作为降低 DSA 的药理学手段。
6 只（6）只恒河猴，先前通过皮肤移植致敏，给予 30mg/kg 抗 RhFcRn IV 单剂量，并测量总 IgG 以及 DSA IgG 的影响，以及 IgM 和保护性免疫。随后，在皮肤移植物供者肾移植的背景下给予 60mg/kg IV。肾移植受者接受 RhATG、他克莫司、MMF 和类固醇维持免疫抑制。
用 DSA 测定法，循环总 IgG 从基线的 100%降低到输注后第 4 天的 32.0%（平均值，SD±10.6）（p<0.05）。T 细胞流式交叉匹配（TFXM）降低至基线的 40.6±12.5%，B 细胞 FXCM 降低至 52.2±19.3%。循环总 IgM 和 DSA IgM 不受治疗影响。病原体特异性抗体（抗-gB 和抗破伤风毒素 IgG）在输注后 14d 显著降低。移植后，循环 IgG 对抗 FcRn mAb 治疗有反应，但 DSA 迅速增加。
靶向 FcRn 介导的 IgG 再循环是降低致敏受者循环供体特异性 IgG 的有效方法，尽管在器官移植中，移植后抗体快速上升的机制不受影响。
