| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Macrophages and dendritic cells recognize not only microorgaisms from outside of the body, but also dying self-cells to eliminate them by engulfment. This phenomenon prevents the release of potentially harmful or immunogenic intracellular materials from dying cells. We have previously shown that milk fat globule-EGF-factor 8 (MFG-E8) is involved in apoptotic cell phagocytosis by phagocytes. MFG-E8 specifically binds to PS exposed on apoptotic cells via C-terminal factor VIII-homologous domains. When MFG-E8 is engaged by apoptotic cells, it binds to α_vβ_3 integrin expressed in phagocytes via a N-terminal EGF-like domain, and promotes the phagocytosis of apoptotic cells. These results indicated that MFG-E8 secreted from activated macrophages binds to apoptotic cells, and brings them to phagocytes for engulfment. We found that one mouse macrophage cell line (BAM3) engulfed apoptotic thymocytes, but not apoptotic WR19L cells, a T-cell line. Monoclonal antibodies that inhibited the phagocy
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tosis of apoptotic thymocytes by BAM3 were identified. Purification of the antigen revealed that it was SHPS-1. CD47,the ligand for SHPS-1,was expressed in mouse thymocytes, but not in WR19L. When WR19L was transformed with CD47,the transformants, after induction of apoptosis, could be phagocytosed by BAM3. The WR19L transformants expressing CD47 were more efficiently engulfed in vivo by splenic dendritic cells than the parental WR19L. Masking of the phosphatidylserine exposed on apoptotic thymocytes inhibited the engulfment. Whereas, the anti-SHPS-1 mAb inhibited not only the engulfment but also the binding of apoptotic cells to phagocytes. These results indicate that macrophages require CD47 and phosphatidylserine on,apoptotic cells for engulfment, and suggest that the interaction between CD47 and SHPS-1 works as a tethering step in the phagocytosis. We also found that Del-1 is highly homologous to MFG-E8,and has a similar function in terms of promoting phagocytosis of apoptotic cells. Less
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