A mimic of p21WAF1/CIP1 ameliorates murine lupus
A mimic of p21WAF1/CIP1 ameliorates murine lupus
复制标题
DOI：
10.4049/jimmunol.175.10.6959
复制
发表时间：
2005-11-15
影响因子：
4.4
通讯作者：
Batteux, F
中科院分区：
文献类型：
--
作者：
Goulvestre, C;Chéreau, C;Batteux, F
系统性红斑狼疮（SLE）是一种进行性自身免疫性疾病，其特征是对dsDNA产生高水平的亲和成熟IgG自身抗体，并可能累及内脏。致病性自身抗体是由核小体组蛋白携带的表位刺激自身反应性T淋巴细胞和B淋巴细胞的活化和增殖引起的。为了抑制自身反应性细胞的增殖和消除SLE的发展，一种新的工具，细胞周期抑制肽疗法，被使用。因此，p21的肽基模拟物（WAF1/CIP1）抑制细胞周期蛋白依赖性激酶4和D型细胞周期蛋白之间的相互作用，从而消除了T细胞对组蛋白的体外增殖反应以及B细胞的T非依赖型和T依赖性增殖反应。（WAF1/CIP1）模拟物也消除了B细胞体外产生总和抗dsdna IgG抗体。同样，p21（WAF1/CIP1）构建体抑制离体T和B细胞对组蛋白的增殖反应，减少活化/记忆B和T脾细胞的数量。脾细胞亚群平衡的改变是由p21（WAF1/CIP1）构建体对活化脾细胞的促凋亡作用引起的。最后，在体内，四次静脉注射p21（WAF1/C1P1）模拟物足以抑制（NZB X NZW）F-1小鼠狼疮样综合征的进展。治疗小鼠的抗dsdna IgG自身抗体水平和肾脏受累的发生率和严重程度低于未治疗小鼠。这些观察结果为SLE的治疗开辟了新的途径，并促使我们评估人类SLE的肽治疗的潜在利益。
Systemic lupus erythematosus (SLE) is a progressive autoimmune disease characterized by the production of high levels of affinity-matured IgG autoantibodies to dsDNA and, possibly, visceral involvement. Pathogenic autoantibodies result from the activation and proliferation of autoreactive T and B lymphocytes stimulated by epitopes borne by nucleosomal histones. To inhibit the proliferation of autoreactive cells and abrogate the development of SLE, a novel tool, cell cycle inhibiting peptide therapy, was used. Thus, a peptidyl mimic of p21(WAF1/CIP1) that inhibits the interaction between cyclin-dependent kinase 4 and type D cyclins abrogated the in vitro proliferative response of T cells to histones and T-independent and T-dependent proliferative responses of B cells. The (WAF1/CIP1) mimic also abrogated the in vitro production of total and anti-dsDNA IgG Abs by B cells. Similarly, the p21(WAF1/CIP1) construct inhibited the ex vivo T and B cell proliferative responses to histones and decreased the numbers of activated/memory B and T spleen cells. The alterations in the balance of spleen cell subsets resulted from proapoptotic effects of the p21(WAF1/CIP1) construct on activated splenocytes. Finally, in vivo, four i.v. injections of the p21(WAF1/C1P1) mimic were sufficient to inhibit the progression of the lupus-like syndrome in (NZB X NZW)F-1 mice. The levels of anti-dsDNA IgG autoantibodies and the incidence and severity of renal involvement were lower in treated mice than in nontreated mice. Those observations open new avenues for the treatment of SLE and prompt us to evaluate the potential interest of peptidic therapy in human SLE.