A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes.
A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes.
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DOI：
10.2337/diabetes.54.6.1763
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发表时间：
2005-06
期刊：
影响因子：
7.7
通讯作者：
Bluestone JA
中科院分区：
文献类型：
--
作者：
Herold KC;Gitelman SE;Masharani U;Hagopian W;Bisikirska B;Donaldson D;Rother K;Diamond B;Harlan DM;Bluestone JA
尽管在动物模型中对自身免疫性糖尿病的了解有所进展，但在改变人类疾病的自然过程（包括进展为胰岛素缺乏）方面进展甚微。免疫抑制剂的研究显示短期有效，但它们没有诱导耐受性，需要持续治疗。在一项随机对照试验中，我们研究了人源化Fc突变抗cd3单克隆抗体hOKT3γ1（Ala-Ala）对新发疾病患者1型糖尿病进展的影响。总的来说，这种药的耐受性很好。单疗程治疗，在诊断后的前6周内，c肽对混合膳食的反应在诊断后1年内保持不变（药物治疗患者在研究开始时的反应为97±9.6%，对照组为53±7.6%,P < 0.01），即使在治疗后2年，c肽对混合膳食的反应也有显著改善（P < 0.02）。c肽反应的改善伴随着HbA1c和胰岛素需求的降低。最后一次给药后2周淋巴细胞计数恢复后，外周血CD8+ t细胞相对数量的增加可以预测药物治疗的临床反应。我们得出结论，在没有持续免疫抑制药物的情况下，使用抗cd3单克隆抗体hOKT3γ1（Ala-Ala）治疗至少2年可改善1型糖尿病患者的c肽反应和临床参数。
Despite advances in understanding autoimmune diabetes in animal models, there has been little progress in altering the natural course of the human disease, which involves progression to insulin deficiency. Studies with immunosuppressive agents have shown short-term effectiveness, but they have not induced tolerance, and continuous treatment is needed. We studied the effects of hOKT3γ1(Ala-Ala), a humanized Fc mutated anti-CD3 monoclonal antibody, on the progression of type 1 diabetes in patients with recent-onset disease in a randomized controlled trial. In general, the drug was well tolerated. A single course of treatment, within the first 6 weeks after diagnosis, preserved C-peptide responses to a mixed meal for 1 year after diagnosis (97 ± 9.6% of response at study entry in drug-treated patients vs. 53 ± 7.6% in control subjects, P < 0.01), with significant improvement in C-peptide responses to a mixed meal even 2 years after treatment (P < 0.02). The improved C-peptide responses were accompanied by reduced HbA1c and insulin requirements. Clinical responses to drug treatment were predicted by an increase in the relative number of CD8+ T-cells in the peripheral blood after the lymphocyte count recovered 2 weeks after the last dose of drug. We conclude that treatment with the anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.