Zoja Carla, Casiraghi Federica, Conti Sara, Corna Daniela, Rottoli Daniela, Cavinato Regiane A, Remuzzi Giuseppe, Benigni Ariela
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Arthritis Rheum. 2007 May;56(5):1629-37. doi: 10.1002/art.22593.
To examine whether the cyclin-dependent kinase (CDK) inhibitor seliciclib ameliorates autoimmune nephritis in (NZB x NZW)F(1) mice.
In experiment 1, NZB x NZW mice received seliciclib (100 mg/kg or 200 mg/kg) or vehicle by gavage, beginning at age 2 months and ending at 8 months of age. In experiment 2, seliciclib (200 mg/kg) was administered alone or combined with low-dose methylprednisolone, starting at age 5 months, when immune complex deposition in the kidney had already occurred. Animals were followed up until all vehicle-treated mice died. In 2 additional groups of NZB x NZW mice treated with seliciclib or vehicle from 2 months of age until 5 months of age, splenocytes were isolated and tested ex vivo for T cell and B cell activity.
Seliciclib, given at an early phase of disease, prolonged survival, delayed the onset of proteinuria and renal function impairment, and protected the kidney against glomerular hypercellularity, tubulointerstitial damage, and inflammation. Combining seliciclib with low-dose methylprednisolone in mice with established disease extended the lifespan and limited proteinuria and renal damage more than treatment with either agent alone. Seliciclib limited immunologic signs of disease, reducing glomerular IgG and C3 deposits and levels of serum anti-DNA antibodies. Moreover, it inhibited ex vivo T cell and B cell proliferative responses to polyclonal stimuli. T cell production of interferon-gamma and interleukin-10 and B cell release of IgG2a were reduced by treatment with seliciclib.
These findings suggest that CDK activity may be a useful target in the treatment of systemic lupus erythematosus. A direct immunomodulatory action of seliciclib on T cells and B cells may be one of the mechanisms underlying the beneficial effects.
研究细胞周期蛋白依赖性激酶（CDK）抑制剂塞利西利是否能改善（新西兰黑鼠×新西兰白鼠）F1小鼠的自身免疫性肾炎。
在实验1中，2月龄的新西兰黑鼠×新西兰白鼠小鼠开始接受塞利西利（100毫克/千克或200毫克/千克）或赋形剂灌胃，直至8月龄结束。在实验2中，5月龄时开始单独给予塞利西利（200毫克/千克）或与低剂量甲泼尼龙联合使用，此时肾脏中已出现免疫复合物沉积。对动物进行随访，直至所有接受赋形剂治疗的小鼠死亡。在另外两组从2月龄至5月龄接受塞利西利或赋形剂治疗的新西兰黑鼠×新西兰白鼠小鼠中，分离脾细胞并在体外检测T细胞和B细胞活性。
在疾病早期给予塞利西利可延长生存期，延迟蛋白尿和肾功能损害的发生，并保护肾脏免受肾小球细胞增多、肾小管间质损伤和炎症的影响。在已发病小鼠中，将塞利西利与低剂量甲泼尼龙联合使用比单独使用任何一种药物更能延长生存期、限制蛋白尿和肾脏损伤。塞利西利限制了疾病的免疫体征，减少了肾小球IgG和C3沉积以及血清抗DNA抗体水平。此外，它还抑制了体外T细胞和B细胞对多克隆刺激的增殖反应。用塞利西利治疗可降低T细胞产生的干扰素-γ和白细胞介素-10以及B细胞释放的IgG2a。
这些发现表明CDK活性可能是系统性红斑狼疮治疗中的一个有用靶点。塞利西利对T细胞和B细胞的直接免疫调节作用可能是其有益作用的潜在机制之一。
