CTLA4-Ig prolongs graft survival specifically in young but not old mice.
CTLA4-Ig prolongs graft survival specifically in young but not old mice.
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CTLA4-IG延长了在年轻而不是老鼠中的移植物生存。
DOI：
10.1111/ajt.16218
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Tullius SG
中科院分区：
文献类型：
--
作者：
Heinbokel T;Quante M;Iske J;Nian Y;Maenosono R;Minami K;Liu Y;Azuma H;Elkhal A;Tullius SG
老年器官移植受者在临床试验中的代表性仍然不足，尽管他们代表着快速增长的人口。在这里，我们评估了CTLA4-Ig的年龄特异性作用，CTLA4-Ig是一种通过CD28阻断apc和T细胞之间共刺激信号的融合蛋白。用CTLA4-Ig处理的幼龄小鼠（2-3个月）的心脏同种异体移植物无限期存活，而80%的老年受体（18个月）在100天后失去移植物。CTLA4-Ig在老年皮肤移植受者中的效果也明显较差。CTLA4-Ig仅在年轻受体中降低CD4+中枢记忆和效应记忆T细胞，并降低全身IFN-γ水平。这些差异对应于老龄小鼠抗原经历的CD4+ T细胞上CD28的表达减少。为了支持这一观点，用慢病毒载体转染诱导CD28恒定表达的老年CD4+ T细胞过继性转移加速了年轻RAG2−/−受体小鼠对异体皮肤移植物的排斥反应。相比之下，Tregs的CD28表达随着年龄的增长而增加，CTLA4-Ig治疗在老年受体中导致Tregs频率降低、增殖受损和抑制能力减弱。这些发现可能被证明具有独特的临床结果免疫抑制老年移植受者的人口增长。
Elderly organ transplant recipients have remained underrepresented in clinical trials, despite representing a rapidly growing population. Here, we assessed age-specific effects of CTLA4-Ig, a fusion protein blocking costimulatory signaling between APCs and T cells through CD28. Cardiac allografts in young mice (2–3 mths) treated with CTLA4-Ig survived indefinitely, while 80% of old recipients (18 mths) had lost their graft after 100 days. CTLA4-Ig was also significantly less effective in older recipients of skin transplants. CTLA4-Ig reduced CD4+ central memory and effector memory T cells and diminished systemic IFN-γ levels only in young recipients. These differences corresponded to a reduced expression of CD28 on antigen-experienced CD4+ T cells in old mice. In support, adoptive transfer of old CD4+ T cells that were transfected with a lentiviral vector inducing constant expression of CD28 accelerated the rejection of allogeneic skin grafts in young RAG2−/− recipient mice. Tregs, in contrast, demonstrated an increased expression of CD28 with aging and CTLA4-Ig treatment in old recipients resulted in reduced frequencies, compromised proliferation and diminished suppressive capacity of Tregs. These findings may prove to have unique clinical consequences for immunosuppression in the growing population of elderly transplant recipients.
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影响因子：
--
作者：
Bernstein, ED;Murasko, DM
通讯作者：
Murasko, DM
CD28在T细胞稳态中共同刺激：最近的观点。
影响因子：
7.2
作者：
Beyersdorf N;Kerkau T;Hünig T
通讯作者：
Hünig T
影响因子：
4
作者：
Heinbokel, Timm;Elkhal, Abdallah;Tullius, Stefan G.
通讯作者：
Tullius, Stefan G.
影响因子：
8.8
作者：
Riella, L. V.;Liu, T.;Chandraker, A.
通讯作者：
Chandraker, A.
影响因子：
3.7
作者：
Denecke C;Bedi DS;Ge X;Kim IK;Jurisch A;Weiland A;Habicht A;Li XC;Tullius SG
通讯作者：
Tullius SG