Epitope-dependent effect of anti-murine TIM-1 monoclonal antibodies on T cell activity and lung immune responses
Epitope-dependent effect of anti-murine TIM-1 monoclonal antibodies on T cell activity and lung immune responses
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DOI：
10.4049/jimmunol.178.4.2249
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发表时间：
2007-02-15
影响因子：
4.4
通讯作者：
Rennert, Paul D.
中科院分区：
文献类型：
--
作者：
D Sizing, Irene;Bailly, Veronique;Rennert, Paul D.
含有TIM基因家族的TAPR基因座与小鼠中特应性炎症的发展有关，并且TIM-1等位基因变异与人类患者群体中特应性的发病率相关。在这项研究中，我们表明，TIM-1通路的操纵影响气道炎症和病理。识别不同表位的抗TIM-1单克隆抗体在小鼠中差异调节OVA诱导的肺部炎症。对这些抗体识别的表位进行了定位，揭示了针对TIM-1的IgV和茎结构域的mAb具有治疗活性。出乎意料的是，识别跨越粘蛋白/茎结构域的外显子4的独特表位的mAb加剧了免疫应答。使用Ag回忆反应研究，我们证明TIM-1途径主要通过调节T（H）2细胞因子的产生起作用。此外，离体细胞实验表明TIM-1活性控制CD 4（+）T细胞活性。这些研究验证了TIM-1基因座与特应性疾病的发展相关的遗传假设，并提出了针对哮喘和其他特应性疾病的新治疗策略。
The TAPR locus containing the TIM gene family is implicated in the development of atopic inflammation in mouse, and TIM-1 allelic variation has been associated with the incidence of atopy in human patient populations. In this study, we show that manipulation of the TIM-1 pathway influences airway inflammation and pathology. Anti-TIM-1 mAbs recognizing distinct epitopes differentially modulated OVA-induced lung inflammation in the mouse. The epitopes recognized by these Abs were mapped, revealing that mAbs to both the IgV and stalk domains of TIM-1 have therapeutic activity. Unexpectedly, mAbs recognizing unique epitopes spanning exon 4 of the mucin/stalk domains exacerbated immune responses. Using Ag recall response studies, we demonstrate that the TIM-1 pathway acts primarily by modulating the production of T(H)2 cytokines. Furthermore, ex vivo cellular experiments indicate that TIM-1 activity controls CD4(+) T cell activity. These studies validate the genetic hypothesis that the TIM-1 locus is linked to the development of atopic disease and suggest novel therapeutic strategies for targeting asthma and other atopic disorders.