Chatenoud Lucienne, Waldmann Herman
INSERM U1013, Necker Hospital, Paris, France.
Rev Diabet Stud. 2012 Winter;9(4):372-81. doi: 10.1900/RDS.2012.9.372. Epub 2012 Dec 28.
Type 1 diabetes (T1D) is a prototypic organ-specific autoimmune disease resulting from the selective destruction of insulin-secreting β-cells within the pancreatic islets of Langerhans. It is caused by an immune-mediated inflammation, involving autoreactive CD4⁺ and CD8⁺ T lymphocytes that infiltrate the islets and initiate insulitis. The use of exogenous insulin is the current standard treatment. However, in spite of significant advances, this therapy is still associated with major constraints, including risk of hypoglycemia and severe degenerative complications. As T1D mainly affects children and young adults, any candidate immune therapy must be safe, and it must avoid a sustained depression of immune responses with all its attendant problems of recurrent infection and drug toxicity. In this context, inducing or restoring immune tolerance to target autoantigens would be the ideal approach. We refer to immune tolerance here as the selective damping of the damaging autoimmune response following a short treatment, while keeping intact the capacity of the host to respond normally to exogenous antigens. The therapeutic approach we discuss in this article originates from attempts to induce tolerance both to soluble antigens and tissue antigens (i.e. alloantigens and autoantigens) by using biological agents that selectively interfere with lymphocyte activation, namely polyclonal and monoclonal anti-T cell antibodies. The challenged dogma was that, in an adult-primed immune system, it was not possible to restore self-tolerance therapeutically without the use of exogenous autoantigen administration. The reality has been that, in diabetes, endogenous host autoantigen can fulfill this role because a significant amount of functioning β-cells remains, even at the time of established hyperglycemia. Experimental results obtained in the 1990s showed that a short-term CD3 antibody treatment in recently diagnosed diabetic non-obese diabetic (NOD) mice induced permanent remission of the disease by restoring self-tolerance. Based on these findings, phase I, II, and III trials were conducted using two distinct humanized Fc-mutated antibodies to human CD3, namely ChAglyCD3 (otelixizumab) and OKT3γ1 Ala-Ala (teplizumab). Overall, when dosing was adequate, the results demonstrated that CD3 antibodies preserved β-cell function very efficiently, maintaining significantly high levels of endogenous insulin secretion in treated patients for up to 24 months after treatment. These data provided the first proof of concept for a long-term therapeutic effect in T1D following a short course administration of a therapeutic agent. Our aim is to review these data and to discuss them in the context of the pitfalls linked to pharmaceutical development, especially in the context of pediatric patients, as in autoimmune diabetes.
1型糖尿病（T1D）是一种典型的器官特异性自身免疫性疾病，由朗格汉斯胰岛内胰岛素分泌β细胞的选择性破坏所致。它是由免疫介导的炎症引起的，涉及自身反应性CD4⁺和CD8⁺T淋巴细胞浸润胰岛并引发胰岛炎。使用外源性胰岛素是目前的标准治疗方法。然而，尽管取得了重大进展，但这种治疗方法仍然存在主要限制，包括低血糖风险和严重的退行性并发症。由于T1D主要影响儿童和年轻人，任何候选免疫疗法都必须安全，并且必须避免免疫反应的持续抑制及其伴随的反复感染和药物毒性问题。在这种情况下，诱导或恢复对靶自身抗原的免疫耐受将是理想的方法。我们在此将免疫耐受定义为在短期治疗后对破坏性自身免疫反应的选择性抑制，同时保持宿主对外源性抗原正常反应的能力。我们在本文中讨论的治疗方法源于尝试通过使用选择性干扰淋巴细胞活化的生物制剂，即多克隆和单克隆抗T细胞抗体，来诱导对可溶性抗原和组织抗原（即同种异体抗原和自身抗原）的耐受。受到挑战的传统观念是，在成年启动的免疫系统中，不使用外源性自身抗原给药就不可能通过治疗恢复自身耐受。实际情况是，在糖尿病中，内源性宿主自身抗原可以发挥这一作用，因为即使在血糖升高确立时，仍有大量有功能的β细胞存在。20世纪90年代获得的实验结果表明，对新诊断的糖尿病非肥胖糖尿病（NOD）小鼠进行短期CD3抗体治疗可通过恢复自身耐受诱导疾病的永久缓解。基于这些发现，使用两种不同的人源化Fc突变抗人CD3抗体，即ChAglyCD3（otelixizumab）和OKT3γ1 Ala-Ala（teplizumab）进行了I期、II期和III期试验。总体而言，当给药充足时，结果表明CD3抗体非常有效地保留了β细胞功能，在治疗后的患者中，内源性胰岛素分泌水平在长达24个月的时间内维持在显著较高水平。这些数据为在T1D中短期给予治疗药物后产生长期治疗效果提供了首个概念验证。我们的目的是回顾这些数据，并在与药物开发相关的陷阱背景下进行讨论，特别是在儿科患者的背景下，就像在自身免疫性糖尿病中一样。
