Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy.
Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy.
复制标题
DOI：
10.1084/jem.20131219
复制
发表时间：
2013-10-21
期刊：
影响因子：
--
通讯作者：
Murphy WJ
中科院分区：
文献类型：
--
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
衰老强烈地促进炎症反应，这可能使癌症治疗后的个体易患致命的系统毒性和病理学，这些毒性和病理学可以通过TNF阻断来部分预防。癌症通常发生在老年人中，免疫疗法（IT）越来越多地应用于这一人群。然而，大多数评估治疗剂的潜在功效和毒性的临床前小鼠肿瘤模型使用年幼小鼠。我们评估了年龄对全身免疫刺激反应的影响。与年轻小鼠相反，给予老年小鼠的全身性癌症IT方案或LPS导致影响多个器官的快速和致命的毒性，这与全身和实质组织内的促炎细胞因子升高相关。这种炎症反应和随年龄增长而增加的发病率与T细胞或NK细胞无关。然而，之前在老年小鼠体内消耗巨噬细胞导致细胞因子水平降低，存活率增加，肝脏组织病理学减少。此外，来自老年小鼠和正常人老年志愿者的巨噬细胞在体外刺激后显示出升高的TNF和IL-6产生。TNF敲除小鼠和体内TNF阻断老年小鼠的治疗导致存活率显著增加和病理学减轻。重要的是，在接受IT的荷瘤老年小鼠中TNF阻断显示出显著的抗肿瘤作用。这些数据证明了巨噬细胞在对全身免疫刺激的年龄相关性高炎症细胞因子应答中的关键作用，并强调了在老年小鼠中进行临床前评估的重要性。
Aging strongly promotes inflammation responses, which may predispose individuals after cancer therapies to lethal system toxicities and pathology that can be partially prevented by TNF blockade. Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.
登录
查看更多内容
影响因子：
20.3
作者：
Ferrucci, L;Corsi, A;Longo, DL
通讯作者：
Longo, DL
DOI：
10.1126/science.1224820
发表时间：
2012-10-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Arthur JC;Perez-Chanona E;Mühlbauer M;Tomkovich S;Uronis JM;Fan TJ;Campbell BJ;Abujamel T;Dogan B;Rogers AB;Rhodes JM;Stintzi A;Simpson KW;Hansen JJ;Keku TO;Fodor AA;Jobin C
通讯作者：
Jobin C
影响因子：
13.5
作者：
Jin, XL;Zimmers, TA;Koniaris, LG
通讯作者：
Koniaris, LG
影响因子：
6.1
作者：
Franceschi, Claudio
通讯作者：
Franceschi, Claudio
影响因子：
3.6
作者：
Grounds, MD;Davies, M;Hodgetts, S
通讯作者：
Hodgetts, S