ABSTRACT

Activation of T cells specific for insulin B chain amino acids 9 to 23 (B:9–23) is essential for the initiation of type 1 diabetes (T1D) in non-obese diabetic mice. We previously reported that peptide/MHC complexes containing optimized B:9–23 mimotopes can activate most insulin-reactive pathogenic T cells. A monoclonal antibody (mAb287) targeting these complexes prevented disease in 30–50% of treated animals (compared to 10% of animals given an isotype control). The incomplete protection is likely due to the relatively low affinity of the antibody for its ligand and limited specificity. Here, we report an enhanced reagent, mAb757, with improved specificity, affinity, and efficacy in modulating T1D. Importantly, mAb757 bound with nanomolar affinity to agonists of both “type A” and “type B” cells and suppressed “type B” cells more efficiently than mAb287. When given weekly starting at 4 weeks of age, mAb757 protected ~70% of treated mice from developing T1D for at least 35 weeks, while mAb287 only delayed disease in 25% of animals under the same conditions. Consistent with its higher affinity, mAb757 was also able to stain antigen-presenting cells loaded with B:9–23 mimotopes in vivo. We conclude that monoclonal antibodies that can block the presentation of pathogenic T cell receptor epitopes are viable candidates for antigen-specific immunotherapy for T1D.

摘要

激活对胰岛素 B 链氨基酸 9 至 23 (B:9-23) 具有特异性的 T 细胞对于非肥胖糖尿病小鼠的 1 型糖尿病 (T1D) 发病至关重要。我们之前曾报道，含有优化的 B:9-23 模拟表位的肽/MHC 复合物可以激活大多数胰岛素反应性致病性 T 细胞。针对这些复合物的单克隆抗体 (mAb287) 在 30-50% 的治疗动物中预防了疾病（相比之下，给予同种型对照的动物为 10%）。不完全保护可能是由于抗体对其配体的亲和力相对较低且特异性有限。在这里，我们报告了一种增强型试剂 mAb757，它在调节 T1D 方面具有更高的特异性、亲和力和功效。重要的，mAb757 以纳摩尔亲和力结合“A 型”和“B 型”细胞的激动剂，并且比 mAb287 更有效地抑制“B 型”细胞。从 4 周龄开始每周给药时，mAb757 保护约 70% 的治疗小鼠免于发展为 T1D 至少 35 周，而 mAb287 在相同条件下仅延迟 25% 动物的疾病。与其更高的亲和力一致，mAb757 还能够染色装载有 B:9-23 模拟表位的抗原呈递细胞体内。我们得出结论，可以阻断致病性 T 细胞受体表位呈递的单克隆抗体是 T1D 抗原特异性免疫治疗的可行候选者。