TY - JOUR
T1 - IL-12 drives IFN-γ-dependent autoimmune kidney disease in MRL-Fas(lpr) mice
AU - Schwarting, A.
AU - Tesch, G.
AU - Kinoshita, K.
AU - Maron, R.
AU - Weiner, H. L.
AU - Kelley, V. Rubin
PY - 1999/12/28
Y1 - 1999/12/28
N2 - 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-γ, the purpose of this study was to determine whether local provision of IL-12 elicits IFN-γ-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 'carder 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-γ-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-γ 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-γ receptors. Furthermore, IFN-γ '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-y- 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.
AB - 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-γ, the purpose of this study was to determine whether local provision of IL-12 elicits IFN-γ-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 'carder 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-γ-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-γ 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-γ receptors. Furthermore, IFN-γ '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-y- 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.
UR - http://www.scopus.com/inward/record.url?scp=0032736187&partnerID=8YFLogxK
M3 - Article
C2 - 10586090
AN - SCOPUS:0032736187
SN - 0022-1767
VL - 163
SP - 6884
EP - 6891
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -