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Use of genetically modified bone marrow‐derived vehicle cells to deliver anti‐inflammatory cytokines to inflamed interstitium

Tubulointerstitial injury is a final common pathway for progressive renal injury in various renal diseases. Several cytokines, infiltrating cells and adhesion molecules are thought to be involved in the development of interstitial injury and fibrosis. However, there is currently no effective therapy for interstitial fibrosis. In this study, we examined the therapeutic efficacy of genetically modified bone marrow-derived CD11bCD18 vehicle cells to deliver anti-inflammatory cytokines to inflamed interstitium in an animal model of unilateral ureteral obstruction (UUO). Vehicle cells that express intracellular adhesion molecule (ICAM)-1 ligands, CD11b and CD18, were obtained from bone marrow cells of DBA/2 mice and adenovirally transduced with interleukin-1 receptor antagonist (IL-1RA) or glucocerebrosidase (GC) cDNA ex vivo. In renal cortex of UUO-treated kidneys, interstitial expression of ICAM-1 and infiltration of macrophages into the interstitium were increased with time from 3 days until 14 days after the operation, while these histological changes were not observed in contralateral untreated kidneys throughout the observation period. In addition, mRNA levels of interleukin-1b (IL-1b) in UUO-treated kidneys were markedly upregulated at day 3 compared with those in contralateral kidneys. Then, UUO-treated DBA/2 mice were injected through the tail vein with either IL-1RA vehicle cells (IL-1RA-treatedmice) or GC vehicle cells (GC-treated mice) at 24h after the operation. Six days after the injection of these vehicle cells, CD11b vehicle cells expressing IL-1RA along with expression of ICAM-1 were observed in the interstitium of UUO-treated kidneys from IL-1RA-treated mice (Fig. 1). In contrast, no obvious CD11bIL-1RA cells were noted in ICAM-1negative contralateral kidneys from these mice. The macrophage infiltration (P<0.001), the expression of ICAM-1 (P<0.005) and a-smooth muscle actin (P= 0.005) in the interstitium of UUO-treated kidneys were significantly decreased in IL-1RA-treated mice compared to GC-treated mice. These findings suggest that IL-1 may have a pivotal role in the development of interstitial injury and our method can site-specifically deliver a functioning gene encoding anti-inflammatory cytokine into inflamed interstitium through interaction of adhesion molecules. This avenue may provide a promising strategy for attenuating progressive interstitial injury.