Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease. Autoantibodies (autoAbs) against double-stranded DNA (ds DNA), the hallmark of lupus, are produced and maintained by the interaction between auto-reactive B cells and CD4+ T cells. This interplay is controlled by the CD28/CD80-86/CTLA-4 axis. Here we investigated whether selective blockade of CD28-CD80/86 co-stimulatory interactions abrogates lupus nephritis development in a murine model of SLE. To this aim, NZB/NZW F1 mice were treated for 3 months, either with an anti-CD28 Fab' fragment or a control Fab'-IgG. The effect of CD28 blockade on lupus nephritis onset, survival, production of anti-ds DNA antibodies and costimulatory molecules was evaluated. CD28 blockade prevented the development of lupus nephritis and prolonged survival during the 3-month treatment and 12 weeks after. Furthermore, the production of anti-ds DNA autoAbs was decreased. Lastly, the protective effect of CD28 blockade was associated with increased intrarenal expression of the immunoregulatory molecule, Indoleamine 2, 3-dioxygenase, of the co-inhibitory receptor programmed cell-Death - 1 (PD-1) and of its ligand programmed death ligand - 1 (PDL-1).In conclusion, CD28 blockade prevented the development of lupus nephritis in NZB/NZW F1 mice. This immunomodulatory strategy is a promising candidate for SLE therapy in humans.

译文

系统性红斑狼疮(SLE)是一种慢性全身性炎症性疾病。通过自身反应性B细胞和CD4 T细胞之间的相互作用,产生并维持针对狼疮的标志性双链DNA(ds DNA)的自身抗体(autoAbs)。这种相互作用是由CD28 / CD80-86 / CTLA-4轴控制的。在这里,我们研究了CD28-CD80 / 86共刺激相互作用的选择性阻断是否消除了狼疮性肾炎在SLE鼠模型中的发展。为了这个目的,将NZB / NZW F1小鼠用抗CD28 Fab'片段或对照Fab'-IgG治疗3个月。评估了CD28阻断对狼疮肾炎发作,生存,抗ds DNA抗体产生和共刺激分子的影响。 CD28阻滞剂在3个月的治疗期间和12周后预防了狼疮性肾炎的发展并延长了生存期。此外,抗ds DNA autoAb的产生减少。最后,CD28阻断的保护作用与免疫调节分子吲哚胺2、3-二加氧酶,共抑制受体编程的细胞死亡-1(PD-1)及其配体编程的死亡配体的肾内表达增加有关。 -1(PDL-1)。总之,CD28阻断可预防NZB / NZW F1小鼠的狼疮性肾炎。这种免疫调节策略是人类SLE治疗的有希望的候选者。

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