| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
In this study, we used genetically modified bone marrow-derived CD11b^+CD18^+ vehicle cells to deliver IL-1 receptor antagonist (IL-ira) for treatment of inflamed, renal interstitium in an animal model of unilateral ureteral obstruction (UUO). Vehicle cells that expressed the ICAM-1 ligands, CD11b and CD 18, were obtained from bone marrow cells of DBAJ2j mice and adenovirally transduced with the IL-ira gene or glucocerebrosidase (GC) gene ex vivo. In kidneys treated to develop UUO, levels of ICAM-i, IL-1β and IL-1 receptor expression increased within 3 days compared to coniralateral untreated kidneys in the same mice. Similarly, the macrophage infiltration in the cortical interstitium increased after 3 days in UUO kidneys, but not untreated kidneys. After UUO developed, DBA/2j mice were injected intravenously with either IL-1ra^+ vehicle cells (IL-1ratreated mice) or GC vehicle cells (OC-treated mice) at 24 hours after UUO. Six days after the injection of these vehicle cells, marked increased of CD11b^+IL-1ra^+ vehicle cells were observed in the ICAM-1-positive interstitium of UUO kidneys from ILira-treated mice. In contrast, no CD11b^+ IL-1ra^+ cells appeared in ICAM-i-negative contralateral kidneys from these mice. Furthermore, the infiltration of macrophages (p<0.001), expression of ICAM-1 (p<z0.005), and presence of a-smooth muscle actin (p=0.005) in the interstitium of UUO kidneys was significantly decreased in IL-ira-treated mice compared to GC-treated mice. These fmdings suggest that IL-1 may contribute to the development of renal interstitial injury and that our method can deliver a functioning gene encoding an anti-inflammatory cytokine gene specifically at that site by interacting with local adhesion molecules.
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