Genetically modified bone marrow-derived vehicle cells site specifically deliver an anti-inflammatory cytokine to inflamed interstitium of obstructive nephropathy.
In this study, we used genetically modified bone marrow-derived CD11b(+)CD18(+) vehicle cells to deliver IL-1 receptor antagonist (IL-1ra) 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 CD18, were obtained from bone marrow cells of DBA/2j mice and adenovirally transduced with the IL-1ra gene or glucocerebrosidase (GC) gene ex vivo. In kidneys treated to develop UUO, levels of ICAM-1, IL-1 beta, and IL-1R expression increased within 3 days compared with contralateral 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 i.v. with either IL-1ra(+) vehicle cells (IL-1ra-treated mice) or GC(+) vehicle cells (GC-treated mice) at 24 h after UUO. Six days after the injection of these vehicle cells, marked increase of CD11b(+) IL-1ra(+) vehicle cells was observed in the ICAM-1-positive interstitium of UUO kidneys from IL-1ra-treated mice. In contrast, no CD11b(+) IL-1ra(+) cells appeared in ICAM-1-negative contralateral kidneys from these mice. Furthermore, the infiltration of macrophages (p < 0.001), expression of ICAM-1 (p < 0.005), and presence of alpha-smooth muscle actin (p = 0.005) in the interstitium of UUO kidneys were significantly decreased in IL-1ra-treated mice compared with GC-treated mice. These findings suggest that IL-1 may contribute to the development of renal interstitial injury and that our method can deliver a functioning gene encoding an antiinflammatory cytokine gene specifically at that site by interacting with local adhesion molecules.
Yamagishi
H
H
Department of Internal Medicine, Division of Nephrology, Jikei University School of Medicine, Tokyo, Japan.
Yokoo
T
T
Imasawa
T
T
Mitarai
T
T
Kawamura
T
T
Utsunomiya
Y
Y
D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D018014:Gene Transfer Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology*; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D009395:Nephritis, Interstitial / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis; D012795:Sialoglycoproteins / Q000008:administration & dosage* / Q000235:genetics*; D015854:Up-Regulation / Q000276:immunology; D014517:Ureteral Obstruction / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control
D018501:Antirheumatic Agents; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D018799:Intercellular Adhesion Molecule-1