| Co-Investigator(Kenkyū-buntansha) |
KUMAGAI Shunich Kobe University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (00153346)
MORINOBU Akio Kobe University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (10294216)
小柴 賢洋 兵庫医科大学, 医学部, 教授 (70301827)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Autoimmune diseases develop as a result of the breakage of tolerance in a combination of genetic backgrounds and various exogenous factors. In lupus nephritis, it is supposed that some unknown factors may trigger and lead to the breakage of peripheral tolerance, resulting in the activation and survival of self-reactive T cells that promote autoimmune process. Recently, B7-CD28 family molecules have revealed their crucial roles in activation and post-activation regulation of T cells. PD-1, one of B7 family receptor and transmitting immunosuppressive signals to lymphocytes, is supposed to be very important in the maintenance of peripheral tolerance, since the murine knockout models have been reported to cause autoimmune-disease-like symptoms. Interestingly, PD-L1 is distributed in epithelia of various peripheral tissues.
We analyzed whether there was abnormality of PD-1/PD-L system in a lupus nephritis model, NZB/W F1 mouse, and examined whether lupus-like nephritis develop when you modify the PD-1/PD-L system. We confirmed the expression of PD-1/PD-L1 in the kidney of NZB/W F1 mouse. PD-1 was expressed on infiltrating lymphocytes, and PD-L1 was on infiltrating lymphocytes, glomerular cells, and tubular cells. Next, we performed intraperitoneal injection of anti-PD-L1 antibody to NZB/W F1 mice for three months. Urine protein appeared in the anti-PD-L1 antibody-treated group earlier than in non-treated group, and about half of mice died early in anti-PD-L1 treated group. Therefore, we concluded that the anti-PD-L1 antibody treatment exacerbated nephritis. In addition, serum interferon γ level was markedly increased in antibody-treated group.
In conclusion, PD-1/PD-L system is closely related to the development of lupus-like nephrits, and we expect that future studies will help to develop a therapeutic method to cure lupus nephritis, or other autoimmune diseases.
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