Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus
Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus
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DOI：
10.1056/nejmoa012864
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发表时间：
2002-05-30
影响因子：
158.5
通讯作者：
Bluestone, JA
中科院分区：
文献类型：
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作者：
Herold, KC;Hagopian, W;Bluestone, JA
背景：1型糖尿病是一种由T淋巴细胞对产生胰岛素的β细胞的致病作用所引起的慢性自身免疫性疾病。先前的临床研究表明，持续的免疫抑制可暂时减缓胰岛素产生的丧失。临床前研究提示，一种抗CD3的单克隆抗体可在发病时逆转高血糖并诱导对复发性疾病的耐受性。
方法：我们研究了一种非激活的抗CD3人源化单克隆抗体——hOKT3γ1（Ala - Ala）对1型糖尿病患者胰岛素产生丧失的影响。在确诊后的6周内，24名患者被随机分配接受单克隆抗体为期14天的单次疗程治疗或不接受抗体治疗，并在患病的第一年内进行研究。
结果：在治疗组的12名患者中，有9名患者在接受单克隆抗体治疗一年后胰岛素产生得以维持或改善，而12名对照组患者中仅有2名有持续的反应（P = 0.01）。对胰岛素反应的治疗效果在确诊后至少持续了12个月。单克隆抗体组的糖化血红蛋白水平和胰岛素剂量也有所降低。未出现严重的副作用，最常见的副作用是发热、皮疹和贫血。临床反应与治疗后30天和90天CD4⁺T细胞与CD8⁺T细胞比值的变化相关。
结论：hOKT3γ1（Ala - Ala）治疗可减轻大多数患者在1型糖尿病发病第一年内胰岛素产生的恶化，并改善代谢控制。抗CD3单克隆抗体的作用机制可能涉及对致病性T细胞的直接作用、调节性细胞群的诱导，或两者兼而有之。
Background: Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease.Methods: We studied the effects of a nonactivating humanized monoclonal antibody against CD3 - hOKT3gamma1(Ala-Ala) - on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease.Results: Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls had a sustained response (P=0.01). The treatment effect on insulin responses lasted for at least 12 months after diagnosis. Glycosylated hemoglobin levels and insulin doses were also reduced in the monoclonal-antibody group. No severe side effects occurred, and the most common side effects were fever, rash, and anemia. Clinical responses were associated with a change in the ratio of CD4+ T cells to CD8+ T cells 30 and 90 days after treatment.Conclusions: Treatment with hOKT3gamma1(Ala-Ala) mitigates the deterioration in insulin production and improves metabolic control during the first year of type 1 diabetes mellitus in the majority of patients. The mechanism of action of the anti-CD3 monoclonal antibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells, or both.