Measuring the Impact of Targeting FcRn-Mediated IgG Recycling on Donor-Specific Alloantibodies in a Sensitized NHP Model.
Measuring the Impact of Targeting FcRn-Mediated IgG Recycling on Donor-Specific Alloantibodies in a Sensitized NHP Model.
复制标题
DOI：
10.3389/fimmu.2021.660900
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Knechtle S
中科院分区：
文献类型：
--
作者：
Manook M;Flores WJ;Schmitz R;Fitch Z;Yoon J;Bae Y;Shaw B;Kirk A;Harnois M;Permar S;Farris AB;Magnani DM;Kwun J;Knechtle S
在移植中，血浆置换和IVIg是减少或清除循环中的供体特异性抗体(DSA)的主要治疗方法，但两者都有局限性。我们试图在致敏的非人灵长类动物(NHP)模型中测试针对新生儿Fc受体(FcRN)的Ig G循环机制的有效性，作为降低DSA的一种药理学手段。6只经皮肤移植致敏的恒河猴，单次注射30 mg/kg的抗RhFcRn IV抗体，除测定IgM和保护性免疫外，还测定了对总抗体和DSA抗体的影响。随后，皮片供者在肾移植时给予60 mg/kg静脉注射。肾移植受者接受RhATG、他克莫司、MMF和类固醇维持免疫抑制。使用DSA分析时，循环总免疫球蛋白从D0的基线100%下降到D4的32.0%(平均SD±10.6)(p<；0.05)。T细胞交叉配型(TFXM)降至基线的40.6±12.5%，B细胞FXCM降至52.2±19.3%。治疗对循环总IgM和DSA IgM无影响。病原体特异性抗体(抗GB和抗破伤风毒素Ig G)在输注后14d显著降低。移植后，抗FcRN单抗治疗对循环免疫球蛋白有反应，但DSA迅速升高。靶向FcRN介导的免疫球蛋白循环是降低致敏受者循环中供体特异性免疫球蛋白的有效手段，尽管在器官移植机制中，移植后抗体的快速上升仍未受到影响。
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.
登录
查看更多内容
影响因子：
7.5
作者：
Robak, Tadeusz;Kazmierczak, Maciej;Jolles, Stephen
通讯作者：
Jolles, Stephen
DOI：
10.1111/ajt.13688
发表时间：
2016-06
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Burghuber CK;Kwun J;Page EJ;Manook M;Gibby AC;Leopardi FV;Song M;Farris AB 3rd;Hong JJ;Villinger F;Adams AB;Iwakoshi NN;Knechtle SJ
通讯作者：
Knechtle SJ
影响因子：
6.7
作者：
Ling LE;Hillson JL;Tiessen RG;Bosje T;van Iersel MP;Nix DJ;Markowitz L;Cilfone NA;Duffner J;Streisand JB;Manning AM;Arroyo S
通讯作者：
Arroyo S
影响因子：
8.8
作者：
Jordan, Stanley C.;Ammerman, Noriko;Vo, Ashley
通讯作者：
Vo, Ashley
影响因子：
6.2
作者：
Roufosse C;Simmonds N;Clahsen-van Groningen M;Haas M;Henriksen KJ;Horsfield C;Loupy A;Mengel M;Perkowska-Ptasińska A;Rabant M;Racusen LC;Solez K;Becker JU
通讯作者：
Becker JU