Generation of T cell responses targeting the reactive metabolite of halothane in mice.
Generation of T cell responses targeting the reactive metabolite of halothane in mice.
复制标题
DOI：
10.1016/j.toxlet.2010.02.009
复制
发表时间：
2010-05-04
影响因子：
3.5
通讯作者：
Ju, Cynthia
中科院分区：
文献类型：
--
作者：
You, Qiang;Cheng, Linling;Ju, Cynthia
免疫介导的药物不良反应（IADR）是临床实践和药物开发中的一个重大问题。由于缺乏动物模型，对 IADR 潜在机制的研究受到阻碍。氟烷会引起严重的过敏性肝炎，其临床特征与 IADR 一致。我们的最终目标是开发氟烷肝炎小鼠模型。有证据表明，针对反应性代谢物（TFA）的肝脏蛋白加合物的适应性免疫反应在发病机制中发挥着重要作用。本研究表明，抗 CD40 抗体和 Toll 样受体 (TLR) 激动剂的组合可作为在小鼠体内产生 TFA 特异性 T 细胞反应的有效佐剂。在用 TFA 小鼠血清白蛋白加合物 (TFA-MSA) 加 CD40/TLR 联合激动剂免疫的小鼠中，T 细胞的 CD4+ 和 CD8+ 亚群均被激活，并且不仅在脾脏中而且还在肝脏中检测到了 TFA 特异性反应。尽管所有三种 TLR 激动剂都能有效引发 BALB/cByJ 小鼠中的 TFA 特异性免疫反应，但只有 PolyI:C 对 DBA/1 小鼠有效，并且没有一种 TLR 激动剂能够帮助 C57BL/6J 小鼠中 TFA 特异性 T 细胞的生成。这一结果与我们之前发现的 BALB/cByJ 小鼠最容易受到氟烷诱导的急性肝损伤的发现相结合，为在未来的研究中使用该菌株提供了基础。总的来说，我们的数据证明成功完成了氟烷肝炎小鼠模型开发中关键的第一步。
Immune-mediated adverse drug reactions (IADRs) represent a significant problem in clinical practice and drug development. Studies of the underlying mechanisms of IADRs have been hampered by the lack of animal models. Halothane causes severe allergic hepatitis with clinical features consistent with an IADR. Our ultimate goal is to develop a mouse model of halothane hepatitis. Evidence suggests that adaptive immune responses targeting liver protein adducts of the reactive metabolite (TFA) play an important role in the pathogenesis. The present study demonstrated that the combination of an anti-CD40 antibody and a Toll-like receptor (TLR) agonist served as a potent adjuvant in generating TFA-specific T cell responses in mice. Both CD4+ and CD8+ subsets of T cells were activated and the TFA-specific responses were detected not only in the spleen but also in the liver of mice immunized with mouse serum albumin adducts of TFA (TFA-MSA) plus the combined CD40/TLR agonist. Whereas all three TLR agonists examined were effective in eliciting TFA-specific immune responses in BALB/cByJ mice, only polyI:C was effective in DBA/1 mice and none of the TLR agonists could aid the generation of TFA-specific T cells in C57BL/6J mice. This result, combined with our previous finding that BALB/cByJ mice were the most susceptible to halothane-induced acute liver injury, provides the basis for employing this strain in future studies. Collectively, our data demonstrated the successful completion of a crucial first step in the development of a murine model of halothane hepatitis.
登录
查看更多内容
影响因子：
4.4
作者：
Bullock, TNJ;Yagita, H
通讯作者：
Yagita, H
影响因子：
4.1
作者：
Masson, MJ;Uetrecht, JP
通讯作者：
Uetrecht, JP
影响因子：
4.4
作者：
Loré, K;Betts, MR;Koup, RA
通讯作者：
Koup, RA
影响因子：
30.5
作者：
Hendriks, J;Gravestein, LA;Borst, J
通讯作者：
Borst, J
影响因子：
15.3
作者：
Rhee, EG;Mendez, S;Seder, RA
通讯作者：
Seder, RA