IL-2 receptor engineering enhances regulatory T cell function suppressed by calcineurin inhibitor.
IL-2 receptor engineering enhances regulatory T cell function suppressed by calcineurin inhibitor.
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DOI：
10.1111/ajt.17181
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发表时间：
2022-12
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--
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调节性T细胞（Treg）治疗在器官移植中的临床试验已经显示出有希望的结果，然而，标准免疫抑制方案的选择仍然存在争议。钙调神经磷酸酶抑制剂（CNI）是器官移植中最常见的免疫抑制剂之一，尽管它们可能通过抑制常规T细胞产生IL-2而对T细胞产生负面影响。作为选择性地替代TcB中的IL-2信号传导的策略，我们引入了工程化的正交IL-2（邻IL-2）细胞因子/细胞因子受体（R）对，其彼此特异性结合但不与其野生型对应物结合。从受体中分离小鼠TCR 4，并在离体扩增期间用ortho IL-2 R β进行逆转录病毒转导。在他克莫司给药的混合造血嵌合体模型中，将转导的TbR（ortho TbR）转移到受体小鼠中。在存在他克莫司的情况下，Ortho IL-2处理显著增加了ortho IL-2 R β（+）Treg群体，而不刺激其他T细胞亚群。所有用他克莫司加邻位IL-2治疗的小鼠即使在他克莫司停药后也能达到心脏移植耐受，而那些单独接受他克莫司治疗的小鼠则不能。这些数据表明，Treg疗法可以通过利用细胞因子受体工程改造而被采用到基于CNI的方案中。
Clinical trials utilizing regulatory T cell (Treg) therapy in organ transplantation have shown promising results, however, the choice of a standard immunosuppressive regimen is still controversial. Calcineurin inhibitors (CNIs) are one of the most common immunosuppressants for organ transplantation, although they may negatively affect Tregs by inhibiting IL-2 production by conventional T cells. As a strategy to replace IL-2 signaling selectively in Tregs, we have introduced an engineered orthogonal IL-2 (ortho IL-2) cytokine/cytokine receptor (R) pair that specifically binds with each other but does not bind with their wild-type counterparts. Murine Tregs were isolated from recipients and retrovirally transduced with ortho IL-2Rβ during ex vivo expansion. Transduced Tregs (ortho Tregs) were transferred into recipient mice in a mixed hematopoietic chimerism model with tacrolimus administration. Ortho IL-2 treatment significantly increased the ortho IL-2Rβ(+) Treg population in the presence of tacrolimus without stimulating other T cell subsets. All the mice treated with tacrolimus plus ortho IL-2 achieved heart allograft tolerance, even after tacrolimus cessation, whereas those receiving tacrolimus treatment alone did not. These data demonstrate that Treg therapy can be adopted into a CNI-based regimen by utilizing cytokine receptor engineering.
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影响因子：
6.2
作者：
Furukawa A;Wisel SA;Tang Q
通讯作者：
Tang Q
影响因子：
14.8
作者：
Bak RO;Dever DP;Porteus MH
通讯作者：
Porteus MH
影响因子：
4.4
作者：
Li, Qiuxia;Shakya, Arvind;Chen, Xinjian
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Chen, Xinjian
影响因子：
7.5
作者：
Hirai, Toshihito;Lin, Po-Yu;Negrin, Robert S.
通讯作者：
Negrin, Robert S.
DOI：
10.1016/s0140-6736(20)30167-7
发表时间：
2020-05-23
期刊：
Lancet (London, England)
影响因子：
--
作者：
Sawitzki B;Harden PN;Reinke P;Moreau A;Hutchinson JA;Game DS;Tang Q;Guinan EC;Battaglia M;Burlingham WJ;Roberts ISD;Streitz M;Josien R;Böger CA;Scottà C;Markmann JF;Hester JL;Juerchott K;Braudeau C;James B;Contreras-Ruiz L;van der Net JB;Bergler T;Caldara R;Petchey W;Edinger M;Dupas N;Kapinsky M;Mutzbauer I;Otto NM;Öllinger R;Hernandez-Fuentes MP;Issa F;Ahrens N;Meyenberg C;Karitzky S;Kunzendorf U;Knechtle SJ;Grinyó J;Morris PJ;Brent L;Bushell A;Turka LA;Bluestone JA;Lechler RI;Schlitt HJ;Cuturi MC;Schlickeiser S;Friend PJ;Miloud T;Scheffold A;Secchi A;Crisalli K;Kang SM;Hilton R;Banas B;Blancho G;Volk HD;Lombardi G;Wood KJ;Geissler EK
通讯作者：
Geissler EK