Schwarting A, Tesch G, Kinoshita K, Maron R, Weiner H L, Kelley V R
Laboratory of Molecular Autoimmune Disease, Renal Division, and Center for Neurological Disease, Brigham and Women's Hospital, Boston, MA 02115, USA.
J Immunol. 1999 Dec 15;163(12):6884-91.
IL-12 is secreted by kidney tubular epithelial cells in autoimmune MRL-Fas(lpr) mice before renal injury and increases with advancing disease. Because IL-12 is a potent inducer of IFN-gamma, the purpose of this study was to determine whether local provision of IL-12 elicits IFN-gamma-secreting T cells within the kidney, which, in turn, incites injury in MRL-Fas(lpr) mice. We used an ex vivo retroviral gene transfer strategy to construct IL-12-secreting MRL-Fas(lpr) tubular epithelial cells (IL-12 "carrier cells"), which were implanted under the kidney capsule of MRL-Fas(lpr) mice before renal disease for a sustained period (28 days). IL-12 "carrier cells" generated intrarenal and systemic IL-12. IL-12 fostered a marked, well-demarcated accumulation of CD4, CD8, and double negative (CD4-CD8- B220+) T cells adjacent to the implant site. We detected more IFN-gamma-producing T cells (CD4 > CD8 > CD4-CD8- B220+) at 28 days (73 +/- 14%) as compared with 7 days (20 +/- 8%) after implanting the IL-12 "carrier cells;" the majority of these cells were proliferating (60-70%). By comparison, an increase in systemic IL-12 resulted in a diffuse acceleration of pathology in the contralateral (unimplanted) kidney. IFN-gamma was required for IL-12-incited renal injury, because IL-12 "carrier cells" failed to elicit injury in MRL-Fas(lpr) kidneys genetically deficient in IFN-gamma receptors. Furthermore, IFN-gamma "carrier cells" elicited kidney injury in wild-type MRL-Fas(lpr) mice. Taken together, IL-12 elicits autoimmune injury by fostering the accumulation of IFN-gamma-secreting CD4, CD8, and CD4-CD8- B220+ T cells within the kidney, which, in turn, promote a cascade of events culminating in autoimmune kidney disease in MRL-Fas(lpr) mice.
在自身免疫性MRL-Fas(lpr)小鼠的肾脏损伤之前，肾小管上皮细胞就会分泌白细胞介素-12（IL-12），且随着疾病进展而增加。由于IL-12是γ干扰素（IFN-γ）的强效诱导剂，本研究的目的是确定局部提供IL-12是否会在肾脏内引发分泌IFN-γ的T细胞，进而在MRL-Fas(lpr)小鼠中引发损伤。我们采用体外逆转录病毒基因转移策略构建分泌IL-12的MRL-Fas(lpr)肾小管上皮细胞（IL-12“载体细胞”），在肾脏疾病发生前将其植入MRL-Fas(lpr)小鼠的肾包膜下持续一段时间（28天）。IL-12“载体细胞”产生肾内和全身的IL-12。IL-12促使在植入部位附近出现明显的、界限分明的CD4、CD8和双阴性（CD4-CD8-B220+）T细胞聚集。与植入IL-12“载体细胞”7天后（20±8%）相比，28天时我们检测到更多产生IFN-γ的T细胞（CD4>CD8>CD4-CD8-B220+）（73±14%）；这些细胞中的大多数正在增殖（60-70%）。相比之下，全身IL-12的增加导致对侧（未植入）肾脏的病理变化弥漫性加速。IL-12引发的肾脏损伤需要IFN-γ，因为IL-12“载体细胞”在IFN-γ受体基因缺陷的MRL-Fas(lpr)肾脏中未能引发损伤。此外，IFN-γ“载体细胞”在野生型MRL-Fas(lpr)小鼠中引发了肾脏损伤。综上所述，IL-12通过促进肾脏内分泌IFN-γ的CD4、CD8和CD4-CD8-B220+T细胞的聚集引发自身免疫性损伤，进而在MRL-Fas(lpr)小鼠中引发一系列最终导致自身免疫性肾病的事件。
