Interleukin-37 improves T-cell-mediated immunity and chimeric antigen receptor T-cell therapy in aged backgrounds.
Interleukin-37 improves T-cell-mediated immunity and chimeric antigen receptor T-cell therapy in aged backgrounds.
复制标题
Interleukin-37 可改善老年背景下的 T 细胞介导的免疫和嵌合抗原受体 T 细胞治疗。
DOI：
10.1111/acel.13309
复制
发表时间：
2021-03
期刊：
影响因子：
7.8
通讯作者：
Henry CJ
中科院分区：
文献类型：
--
作者：
Hamilton JAG;Lee MY;Hunter R;Ank RS;Story JY;Talekar G;Sisroe T;Ballak DB;Fedanov A;Porter CC;Eisenmesser EZ;Dinarello CA;Raikar SS;DeGregori J;Henry CJ
与老龄化相关的先天和适应性免疫反应的下降是有充分证据的，并对日益增长的老龄化人口构成风险，预计到2050年，老龄化人口将占世界人口的40%以上。已努力提高老年人口的免疫力；然而，尚未普遍制定安全有效的方案来实现这一目标。与衰老相关的慢性炎症被认为会损害老龄小鼠和人类的免疫力。白介素37(IL-37)是一种有效的抗炎细胞因子，我们提供的数据表明，人单核细胞中IL-37基因的表达水平随着年龄的增长而显著下降。此外，我们证明，在老年小鼠中转基因表达IL-37可以减少或防止与衰老相关的慢性炎症、脾肿大以及骨髓和脾中髓系细胞(巨噬细胞和树突状细胞)的聚集。此外，我们发现，IL-37的表达降低了程序性细胞死亡蛋白1(PD-1)的表面表达，并增加了衰老T细胞产生的细胞因子。当老年小鼠接受重组IL-37(rIL-37)而不是对照免疫球蛋白(对照Ig)处理时，T细胞功能的改善与年轻时CD4+T细胞中Pdcd1、Lat和STAT4基因表达水平以及CD8+T细胞中Lat基因表达水平的恢复相一致。重要的是，在老化的嵌合抗原受体(CAR)T细胞中也观察到了IL-37介导的老化内源性T细胞的年轻化，其中功能的改善显著延长了移植白血病细胞的小鼠的存活时间。总而言之，这些数据证明了IL-37在增强衰老T细胞功能方面的效力，并突出了其克服衰老相关免疫衰老的治疗潜力。衰老与慢性炎症(炎症)和免疫衰老有关，这被认为是促进癌症发展的因素。在这里，我们证明了用抗炎细胞因子白介素37(IL-37)治疗老年小鼠可以消除炎症，抑制老年T细胞上免疫抑制蛋白的表达，并使效应器反应恢复活力。重要的是，我们发现重组IL-37治疗增强了老化的CAR T细胞在白血病小鼠模型中的疗效。
Aging‐associated declines in innate and adaptive immune responses are well documented and pose a risk for the growing aging population, which is predicted to comprise greater than 40 percent of the world's population by 2050. Efforts have been made to improve immunity in aged populations; however, safe and effective protocols to accomplish this goal have not been universally established. Aging‐associated chronic inflammation is postulated to compromise immunity in aged mice and humans. Interleukin‐37 (IL‐37) is a potent anti‐inflammatory cytokine, and we present data demonstrating that IL‐37 gene expression levels in human monocytes significantly decline with age. Furthermore, we demonstrate that transgenic expression of interleukin‐37 (IL‐37) in aged mice reduces or prevents aging‐associated chronic inflammation, splenomegaly, and accumulation of myeloid cells (macrophages and dendritic cells) in the bone marrow and spleen. Additionally, we show that IL‐37 expression decreases the surface expression of programmed cell death protein 1 (PD‐1) and augments cytokine production from aged T‐cells. Improved T‐cell function coincided with a youthful restoration of Pdcd1, Lat, and Stat4 gene expression levels in CD4+ T‐cells and Lat in CD8+ T‐cells when aged mice were treated with recombinant IL‐37 (rIL‐37) but not control immunoglobin (Control Ig). Importantly, IL‐37‐mediated rejuvenation of aged endogenous T‐cells was also observed in aged chimeric antigen receptor (CAR) T‐cells, where improved function significantly extended the survival of mice transplanted with leukemia cells. Collectively, these data demonstrate the potency of IL‐37 in boosting the function of aged T‐cells and highlight its therapeutic potential to overcome aging‐associated immunosenescence. Aging is associated with chronic inflammation (inflammaging) and immunosenescence, which are thought to promote cancer development. Here, we demonstrate that treating aged mice with the anti‐inflammatory cytokine interleukin‐37 (IL‐37) abrogates inflammaging, suppresses the expression of immunoinhibitory proteins on aged T‐cells, and rejuvenates effector responses. Importantly, we found that recombinant IL‐37 treatment augments the efficacy of aged CAR T‐cells in murine models of leukemia.
登录
查看更多内容
DOI：
10.1084/jem.20131219
发表时间：
2013-10-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bouchlaka MN;Sckisel GD;Chen M;Mirsoian A;Zamora AE;Maverakis E;Wilkins DE;Alderson KL;Hsiao HH;Weiss JM;Monjazeb AM;Hesdorffer C;Ferrucci L;Longo DL;Blazar BR;Wiltrout RH;Redelman D;Taub DD;Murphy WJ
通讯作者：
Murphy WJ
DOI：
10.1084/jem.185.9.1573
发表时间：
1997-05-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cope AP;Liblau RS;Yang XD;Congia M;Laudanna C;Schreiber RD;Probert L;Kollias G;McDevitt HO
通讯作者：
McDevitt HO
影响因子：
20.3
作者：
Boulos, Nidal;Mulder, Heather L.;Williams, Richard T.
通讯作者：
Williams, Richard T.
DOI：
10.4049/jimmunol.1402550
发表时间：
2015-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bally AP;Lu P;Tang Y;Austin JW;Scharer CD;Ahmed R;Boss JM
通讯作者：
Boss JM
影响因子：
--
作者：
Bayraktar, Soley;Batoo, Sameer;Gluck, Stefan
通讯作者：
Gluck, Stefan