Effect of Ex Vivo-Expanded Recipient Regulatory T Cells on Hematopoietic Chimerism and Kidney Allograft Tolerance Across MHC Barriers in Cynomolgus Macaques.
Effect of Ex Vivo-Expanded Recipient Regulatory T Cells on Hematopoietic Chimerism and Kidney Allograft Tolerance Across MHC Barriers in Cynomolgus Macaques.
复制标题
过体扩展的受体调节T细胞对cynomolgus猕猴中MHC障碍的造血嵌合体和肾脏同种异体耐受性的影响。
DOI：
10.1097/tp.0000000000001559
复制
发表时间：
2017-02
期刊：
影响因子：
6.2
通讯作者：
Sykes M
中科院分区：
文献类型：
--
作者：
Duran-Struuck R;Sondermeijer HP;Bühler L;Alonso-Guallart P;Zitsman J;Kato Y;Wu A;McMurchy AN;Woodland D;Griesemer A;Martinez M;Boskovic S;Kawai T;Cosimi AB;Yang YG;Hu Z;Wuu CS;Slate A;Mapara M;Baker S;Tokarz R;D'Agati V;Hammer S;Pereira M;Lipkin WI;Wekerle T;Levings M;Sykes M
受体调节性T细胞(Treg)的输注促进了接受最低限度条件下异基因骨髓移植的小鼠持久的混合造血嵌合体和同种异体移植耐受。我们在食蟹猴模型中应用了这一策略。多克隆扩增的CD4+CD25High Treg在体外对FoxP3的高表达有较强的抑制作用。8只猴子接受了使用或不使用Treg输注的非清髓性预适应和MHC不匹配的骨髓移植。在骨髓移植后4个月进行肾移植(取自相同的骨髓移植供者)，在没有免疫抑制的情况下评估供者特异性耐受性。在接受骨髓移植而不接受Treg的动物(N=3)中，出现了短暂的混合嵌合体，而没有显著的T细胞嵌合体。相比之下，可评估的Treg+BMT受者中有2人在骨髓移植后长达335天的所有谱系中表现出嵌合体，包括T细胞。重要的是，在长期存活的动物中，90%的供体T细胞是CD45RA+CD31+，这表明他们是新的胸腺移民。在这只动物中，延迟(到4个月)的供体肾移植在没有免疫抑制的情况下接受了294天，而非Treg BMT的受者在3-4周内拒绝了延迟的供体肾脏。早期巨细胞病毒重新激活和治疗与嵌合体早期失败有关，与Treg治疗无关。我们的研究提供了原理证明，在没有CMV早期激活(和BM毒性抗病毒治疗)的情况下，宿主Treg的联合移植可以促进长期和高水平的多系同种异体嵌合体和对供者的强大耐受性。
Infusion of recipient regulatory T cells (Treg) promotes durable mixed hematopoietic chimerism and allograft tolerance in mice receiving allogeneic BMT with minimal conditioning. We applied this strategy in a Cynomolgus macaque model. CD4+CD25high Treg that were polyclonally expanded in culture were highly suppressive in vitro and maintained high expression of FoxP3. Eight monkeys underwent nonmyeloablative conditioning and MHC-mismatched BMT with or without Treg infusion. Renal transplantation (from the same BMT donor) was performed 4 months post-BMT without immunosuppression to assess for robust donor-specific tolerance. Transient mixed chimerism, without significant T cell chimerism, was achieved in the animals that received BMT without Treg (N=3). In contrast, the 2 of 5 recipients of Treg + BMT that were evaluable displayed chimerism in all lineages, including T cells, for up to 335 days post-BMT. Importantly, in the animal that survived long-term, >90% of donor T cells were CD45RA+CD31+, suggesting they were new thymic emigrants. In this animal, the delayed (to 4 months) donor kidney graft was accepted >294 days without immunosuppression, whereas non-Treg BMT recipients rejected delayed donor kidneys within 3-4 weeks. Early cytomegalovirus reactivation and treatment was associated with early failure of chimerism, regardless of Treg administration. Our studies provide proof-of-principle that, in the absence of early CMV reactivation (and BM-toxic antiviral therapy), co-transplantation of host Treg can promote prolonged and high levels of multilineage allogeneic chimerism and robust tolerance to the donor.