Quezada Sergio A, Eckert Maria, Adeyi Oyedele A, Schned Alan R, Noelle Randolph J, Burns Christopher M
Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Arthritis Rheum. 2003 Sep;48(9):2541-54. doi: 10.1002/art.11230.
Treatment with anti-CD154 antibody is known to ameliorate murine lupus nephritis when given early in the disease. The aims of this study were to identify the mechanism of this early effect, to determine whether late anti-CD154 treatment could halt established nephritis, and, if so, to examine potential mechanisms of late efficacy.
We studied the effects of anti-CD154 treatment on autoantibody production and immune complex deposition, renal pathology, survival, and renal cytokine and chemokine messenger RNA (mRNA) expression both in (NZB x NZW)F(1) mice (BW mice) and in NZM.2410 mice.
Early treatment with anti-CD154 produced long-term survival in BW mice, with abrogation of renal immune complex deposition for months after treatment was stopped. Late anti-CD154 treatment, started after development of nephritis, could halt disease in approximately 40% of mice. In some mice, proteinuria could be reversed repeatedly with sequential courses of anti-CD154 antibody. The remissions induced by late treatment with anti-CD154 occurred despite ongoing renal immune complex deposition. In preliminary studies, responding mice had rapid reductions in renal mRNA for transforming growth factor beta, interleukin-10, and tumor necrosis factor alpha.
Amelioration of murine lupus by anti-CD154 therapy is mediated by distinct mechanisms in early versus late intervention. We postulate that anti-CD154 therapy prevents autoantibody production and renal immune complex deposition in the early, induction phase and limits secondary tissue damage in situ in the late, effector phase. These data demonstrate that CD40-CD154 interactions are critical for the maintenance of autoimmunity and suggest a potential role for anti-CD154 as a therapeutic agent in established human lupus.
已知在疾病早期给予抗CD154抗体治疗可改善小鼠狼疮性肾炎。本研究的目的是确定这种早期效应的机制，确定晚期抗CD154治疗是否能阻止已形成的肾炎，若能，则研究晚期疗效的潜在机制。
我们研究了抗CD154治疗对（NZB×NZW）F1小鼠（BW小鼠）和NZM.2410小鼠自身抗体产生、免疫复合物沉积、肾脏病理学、生存率以及肾脏细胞因子和趋化因子信使核糖核酸（mRNA）表达的影响。
早期给予抗CD154治疗可使BW小鼠长期存活，在治疗停止后数月内肾脏免疫复合物沉积消失。在肾炎发生后开始的晚期抗CD154治疗可使约40%的小鼠病情停止发展。在一些小鼠中，蛋白尿可通过连续给予抗CD154抗体疗程反复逆转。尽管肾脏持续存在免疫复合物沉积，但晚期抗CD154治疗仍可诱导缓解。在初步研究中，有反应的小鼠肾脏中转化生长因子β、白细胞介素-10和肿瘤坏死因子α的mRNA迅速减少。
抗CD154治疗改善小鼠狼疮的机制在早期和晚期干预中有所不同。我们推测，抗CD154治疗在早期诱导阶段可预防自身抗体产生和肾脏免疫复合物沉积，在晚期效应阶段可限制原位继发性组织损伤。这些数据表明CD40-CD154相互作用对自身免疫的维持至关重要，并提示抗CD154作为一种治疗药物在已确诊的人类狼疮中具有潜在作用。
