| Co-Investigator(Kenkyū-buntansha) |
KANAI Takanori Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Assistant Professor, 医学部附属病院, 講師 (40245478)
OOOKA Shinya Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Instructor, 医学部附属病院, 助手 (90361691)
WATANABE Mamoru Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Professor, 大学院医歯学総合研究科, 教授 (10175127)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2005: ¥2,900,000 (Direct Cost: ¥2,900,000)
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| Research Abstract |
Leukocytapheresis using a leukocyte removal filter (known as lymphocytapheresis, LCAP) has been applied to the treatment of ulcerative colitis (UC) in recent years. We here aim to clarify how LCAP therapy modifies inflammatory responses by modulating circulating monocytes and lymphocytes. Mononuclear cells were isolated from blood before and after LCAP treatment, and expression profiles of various immune cells (naive vs. memory, regulatory CD4^+CD25^<bright> vs. non-regulatory CD4^+CD25^- T cells, CD14^+CD16^- vs. CD14^<dull>CD16^+ monocytes, and effector-memory CD4^+CD45RO^+CD62L^- vs. central-memory CD4^+CD45RO^+CD62L^+ cells) were evaluated by FACS. To assess immunological differences between CD14^+CD16^- and CD14^<dull>CD16^+ monocytes, expression of TNF-α, IL-6, IL-12, IL-18, TLR2, TLR4, and other activation markers including HLA-DR, CD80 and CD86, as well as cytokine profiles were analyzed. We found that LCAP treatment selectively removed CD14^<dull>CD16^+ monocytes, which prefer
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entially produce proinflammtory TNF-α and IL-12, and express HLA-DR, CD80, CD86, and TLR2 compared with the major fraction of CD14^+CD16^- monocytes. In addition, the ratio was significantly lower after LCAP therapy. However, the CD4^+CD25^<bright>/total CD4^+ ratio did not change. The findings reveal the real target of proinflammatory CD14^<dull>CD16^+ monocytes, removed during LCAP treatment for UC, and that LCAP might be used as an extracorporeal anti-TNF-α/IL-12 therapy, expanding the clinical applications of this procedure to include the treatment of Crohn's disease. Furthermore, the fact that LCAP selectively removed effector-memory type of CD4^+ T cells rather than central-memory CD4^+ T cells indicates that LCAP selectively removes gut-homing colitotgenic CD4^+ T cells. Taken together, we propose that lymphocytapheresis rank up extracorporeal therapy not only to shut down the circulation of colitogenic immune cells in UC, but also possibly to decrease side effects that are usually seen in conventional drug therapies. Now, we are developing 2^<nd> generated absorbing fibers that are conjugated commercially used anti-TNF-α mAb to remove TNF-α-expressing cells more selectively and effectively. Less
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