Tim3 Is Upregulated and Protective in Nephrotoxic Serum Nephritis
Tim3 Is Upregulated and Protective in Nephrotoxic Serum Nephritis
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DOI：
10.2353/ajpath.2010.090859
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发表时间：
2010-04-01
影响因子：
6
通讯作者：
Rosenkranz, Alexander R.
中科院分区：
文献类型：
--
作者：
Schroll, Andrea;Eller, Kathrin;Rosenkranz, Alexander R.
T细胞免疫球蛋白和粘蛋白-3（Tim 3）主要表达于辅助性T淋巴细胞（T-H）的细胞表面，负调节T-H-1型（T-H-1）应答。由于阻断Tim 3可增强T-H-1依赖性疾病的活动性，我们研究了Tim 3是否参与T-H-1依赖性肾毒性肾炎（NTS）的发病机制。我们首先评估了诱导肾毒性血清肾炎（NTS）后小鼠中的Tim 3表达，然后研究了抗Tim 3治疗对NTS过程长达7天的影响。而Tim 3表达在对照组小鼠中检测不到，我们发现在NTS诱导后1周、4周和8周，肾脏中的Tim 3表达显著增加，但引流淋巴结中的Tim 3表达没有增加。浸润到NTS小鼠肾脏的表达Tim 3的细胞被证明是CD 4（+）T细胞，而不是CD 8（+）细胞毒性T细胞和树突状细胞。阻断性抗Tim 3抗体的施用加重肾炎，如通过显著增加的白蛋白尿、相应的组织学变化和肾损伤分子脂质运载蛋白-2的表达增加所示。平行地，检测到抗Tim 3处理的小鼠的肾脏中浸润T细胞、巨噬细胞和巨噬细胞促炎细胞因子形成的增加以及增殖和凋亡的增加。总之，我们提供了第一个证据表明，Tim 3在NTS的肾脏中上调，并且Tim 3在疾病过程中发挥保护作用。(Am J Pathol 2010，176：1716-1724; DOI：10.2353/ajpath.2010.090859）
T cell immunoglobulin and mucin protein-3 (Tim3) is mainly expressed on the cell surface of T-helper lymphocytes (T-H) that negatively regulates T-H-type 1 (T-H-1) responses. Because blockade of Tim3 aggravates disease activity in T-H-1-dependent diseases, we investigated whether Tim3 is involved in the pathogenesis of the T-H-1-dependent nephrotoxic nephritis (NTS). We first evaluated Tim3 expression in mice after induction of nephrotoxic serum nephritis (NTS) and then studied the effects of anti-Tim3 treatment toward the course of NTS for up to seven days. Whereas Tim3 expression was undetectable in control mice, we found significantly increased Tim3 expression in kidneys, but not in draining lymph nodes, at one, four, and eight weeks after induction of NTS. Tim3-expressing cells that infiltrated kidneys of mice subjected to NTS turned out to be CD4(+) T cells rather than CD8(+) cytotoxic T cells and dendritic cells. Administration of a blocking anti-Tim3 antibody aggravated nephritis as shown by significantly increased albuminuria, respective histological changes, and increased expression of the kidney injury molecule lipocalin-2. In parallel, an increase of infiltrating T cells, macrophages, and macrophage pro-inflammatory cytokine formation as well as increased proliferation and apoptosis in kidneys of anti-Tim3 treated mice was detected. Together, we provide the first evidence that Tim3 is up-regulated in kidneys in NTS and that Tim3 exerts protective roles in the course of disease. (Am J Pathol 2010, 176:1716-1724; DOI: 10.2353/ajpath.2010.090859)