拮抗TIM-1可以阻断人源化变应性哮喘小鼠模型的疾病进展
2010/12/07
人和小鼠的相关研究揭示了TIM基因与几种变应性疾病有关。TIM-1是表达于T细胞表面的Ⅰ型膜蛋白，经由TIM-1的刺激信号可以调节T细胞的活化状态。DC可以通过TIM-1发生与T细胞之间的相互作用。此外，TIM-1还是磷脂酰丝氨酸识别分子，已发现相应的几种蛋白配体。因为TIM-1有多种结合配体，Sanchaita Sriwal Sonar等认为TIM-1的活性较为复杂。
为明确TIM-1的功能，Sanchaita Sriwal Sonar等制备了针对TIM-1IgV结构域所形成的裂缝区域的单克隆抗体，并证实封闭此区域可以拮抗TIM-1与特异配体及细胞的结合。此TIM-1抗体对人源化SCID哮喘小鼠模型有治疗作用，它可以减轻炎症和气道高反应性。进一步的研究证实，TIM-1抗体的治疗作用与其抑制Th2细胞增殖和细胞因子产生有关。这表明TIM-1通路对人源化疾病模型中活化T细胞的功能有重要影响。
因此，TIM-1拮抗剂对哮喘及其他免疫相关疾病有较强的治疗作用。
（欧阳海峰 第四军医大学西京医院呼吸内科 710032 摘译）
（J Clin Invest. 2010;120(8):2767-2781.）
Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma.
Sonar SS, Hsu YM, Conrad ML, Majeau GR, Kilic A, Garber E, Gao Y, Nwankwo C, Willer G, Dudda JC, Kim H, Bailly V, Pagenstecher A, Rennert PD, Renz H.
Studies in mice and humans have revealed that the T cell, immunoglobulin, mucin (TIM) genes are associated with several atopic diseases. TIM-1 is a type I membrane protein that is expressed on T cells upon stimulation and has been shown to modulate their activation. In addition to a recently described interaction with dendritic cells, TIM-1 has also been identified as a phosphatidylserine recognition molecule, and several protein ligands have been proposed. Our understanding of its activity is complicated by the possibility that TIM-1 possesses multiple and diverse binding partners. In order to delineate the function of TIM-1, we generated monoclonal antibodies directed to a cleft formed within the IgV domain of TIM-1. We have shown here that antibodies that bind to this defined cleft antagonize TIM-1 binding to specific ligands and cells. Notably, these antibodies exhibited therapeutic activity in a humanized SCID model of experimental asthma, ameliorating inflammation, and airway hyperresponsiveness. Further experiments demonstrated that the effects of the TIM-1-specific antibodies were mediated via suppression of Th2 cell proliferation and cytokine production. These results demonstrate that modulation of the TIM-1 pathway can critically influence activated T cells in a humanized disease model, suggesting that TIM-1 antagonists may provide potent therapeutic benefit in asthma and other immune-mediated disorders.
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