IL-12 deficiency in MRL-Faslpr mice delays nephritis and intrarenal IFN-γ expression, and diminishes systemic pathology
IL-12 deficiency in MRL-Faslpr mice delays nephritis and intrarenal IFN-γ expression, and diminishes systemic pathology
复制标题
DOI：
10.4049/jimmunol.170.7.3915
复制
发表时间：
2003-04-01
影响因子：
4.4
通讯作者：
Kelley, VR
中科院分区：
文献类型：
--
作者：
Kikawada, E;Lenda, DM;Kelley, VR
MRL-Fas（lpr）小鼠的自身免疫性疾病的特征在于致命性肾炎、全身病理学和自身抗体，模仿人类狼疮。我们先前报道了1）肾内IL-12通过促进肾内IFN-γ分泌性T细胞的积累而诱发肾炎，和2）IFN-γ受体缺陷的MRL-Fas（lpr）小鼠免于肾炎。因此，我们假设在MRL-Fas（lpr）小鼠中消除IL-12减少IFN-γ分泌细胞，从而防止全身性病理。为此，我们构建了IL-12（-/-）缺陷型MRL-Fas（lpr）菌株。我们确定，与野生型（WT）品系（5月龄）相比，IL-12（-/-）小鼠的肾小球和间质（而非血管周围）肾脏病理学有所减轻。同样，全身病理学（肺、泪腺和唾液腺、皮肤和淋巴结病）减轻。在IL-12（-/-）MRL-Fas（lpr）肾脏中，T细胞（CD 4（+）、CD 8（+）、CD 4（-）CD 8（-）B220（+））和巨噬细胞的肾内积聚显著减少。我们确定，与WT肾相比，在IL-12（-/-）保护的肾中存在较少的IFN-γ转录物（>70%）。类似地，与来自WT肾的细胞相比，当用IL-12和IL-18刺激时，从IL-12（-/-）MRL-Fas（lpr）肾增殖的细胞产生显著更少的IFN-γ，并且我们在这些IL-12（-/-）MRL-Fas（lpr）肾中检测到更少的产生IFN-γ的CD 8和B220 T细胞。值得注意的是，在IL-12（-/-）MRL-Fas（lpr）小鼠中存活适度延长。尽管濒死IL-12（-/-）MRL-Fas（lpr）小鼠的肺、泪腺和唾液腺病理学仍有所降低，但肾脏病理学和IFN-γ表达与WT品系相当。因此，我们认为IL-12是狼疮多个组织的治疗靶点;然而，单独阻断IL-12不足以提供持久的保护免受狼疮肾炎。
Autoimmune disease in MRL-Fas(lpr) mice is characterized by fatal nephritis, systemic pathology, and autoantibodies, mimicking human lupus. We previously reported that 1) intrarenal IL-12 elicits nephritis by fostering the accumulation of intrarenal IFN-gamma-secreting T cells, and 2) MRL-Fas(lpr) mice deficient in the IFN-gamma receptor were spared from nephritis. Therefore, we hypothesized that eliminating IL-12 in MRL-Fas(lpr) mice reduces IFN-gamma-secreting cells and thereby prevents systemic pathology. For this purpose, we constructed am IL-12p40-deficient MRL-Fas(lpr) (IL-12(-/-)) strain. We determined that glomerular and interstitial, but not perivascular, renal pathology were decreased in IL-12(-/-) mice vs the wild-type (WT) strain (5 mo of age). Similarly, systemic pathology (lung, lacrimal and salivary glands, skin, and lymphadenopathy) was diminished. The intrarenal accumulation of T cells (CD4(+), CD8(+), CD4(-)CD8(-)B220(+)) and macrophages was dramatically reduced in IL-12(-/-) MRL-Fas(lpr) kidneys. We determined that there were fewer IFN-gamma transcripts (>70%) in the IL-12(-/-) protected kidneys compared with the WT kidneys. Similarly, cells propagated from IL-12(-/-) MRL-Fas(lpr) kidneys generated substantially less IFN-gamma when stimulated with IL-12 and IL-18 compared with those from WT kidneys, and we detected fewer CD8 and B220 T cells producing IFN-gamma in these IL-12(-/-) MRL-Fas(lpr) kidneys. Of note, survival was modestly extended in the IL-12(-/-) MRL-Fas(lpr) mice. While lung and lacrimal and salivary gland pathology remained reduced in moribund IL-12(-/-) MRL-Fas(lpr) mice, renal pathology and IFN-gamma expression were equivalent to those in the WT strain. Thus, we suggest that IL-12 is a therapeutic target for multiple tissues in lupus; however blocking IL-12 alone is not sufficient to confer enduring protection from lupus nephritis.