Laurent Laetitia, Le Fur Awena, Bloas Rozenn Le, Néel Mélanie, Mary Caroline, Moreau Anne, Poirier Nicolas, Vanhove Bernard, Fakhouri Fadi
INSERM UMR 1064, Nantes, France.
Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.
Eur J Immunol. 2017 Aug;47(8):1368-1376. doi: 10.1002/eji.201746923. Epub 2017 Jul 10.
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.
系统性红斑狼疮（SLE）是一种慢性全身性炎症性疾病。针对双链DNA（dsDNA）的自身抗体（自身抗体）是狼疮的标志，由自身反应性B细胞和CD4 T细胞之间的相互作用产生并维持。这种相互作用由CD28/CD80 - 86/CTLA - 4轴控制。在这里，我们研究了在SLE小鼠模型中，选择性阻断CD28 - CD80/86共刺激相互作用是否能消除狼疮性肾炎的发展。为此，用抗CD28 Fab'片段或对照Fab'-IgG对NZB/NZW F1小鼠进行了3个月的治疗。评估了CD28阻断对狼疮性肾炎发病、存活率、抗dsDNA抗体产生和共刺激分子的影响。CD28阻断可预防狼疮性肾炎的发展，并在3个月的治疗期间及之后的12周内延长生存期。此外，抗dsDNA自身抗体的产生减少。最后，CD28阻断的保护作用与肾内免疫调节分子吲哚胺2,3 - 双加氧酶、共抑制受体程序性细胞死亡-1（PD - 1）及其配体程序性死亡配体-1（PDL - 1）的表达增加有关。总之，CD28阻断可预防NZB/NZW F1小鼠狼疮性肾炎的发展。这种免疫调节策略是人类SLE治疗的一个有前景的候选方法。
