EpiVax, Inc., 146 Clifford Street, Providence, RI 02903, USA.
J Diabetes Res. 2013;2013:621693. doi: 10.1155/2013/621693. Epub 2013 Apr 23.
HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called "Tregitopes") have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigens ex vivo and on the modulation of type 1 diabetes (T1D) in a murine model in vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on T cell responses, we evaluated the effect of Tregitope treatment in DO11.10 mice. Upregulation of FoxP3 in KJ1-26-stained OVA-specific CD4(+) T cells was observed following treatment of DO11.10 mice with Tregitopes, along with reductions in anti-OVA Ig and T effector responses. In ex vivo studies of human T cells, peripheral blood mononuclear cells' (PBMC) responses to GAD65 epitopes in the presence and absence of Tregitope were variable. Suppression of immune responses to GAD65 epitopes ex vivo by Tregitope appeared to be more effective in assays using PBMC from a newly diagnosed diabetic subject than for other more established diabetic subjects, and correlation of the degree of suppression with predicted HLA restriction of the Tregitopes was confirmed. Implementation of these defined regulatory T cell epitopes for therapy of T1D and other autoimmune diseases may lead to a paradigm shift in disease management.
HLA Ⅱ类限制性调节性 T 细胞（Treg）表位在 IgG 中被报道可以通过刺激天然 Treg（nTregs）的扩增来抑制共给药抗原的免疫反应。在这里，我们评估了它们对胰岛细胞抗原的人免疫反应的影响，并在体内的小鼠模型中评估了它们对 1 型糖尿病（T1D）的调节作用。Tregitope 与 T1D 抗原共同给药可延迟高血糖的发生，并降低 NOD 小鼠糖尿病的发病率。即使在疾病发生后，也可以观察到糖尿病的抑制。为了测量 Tregitope 治疗对 T 细胞反应的影响，我们在 DO11.10 小鼠中评估了 Tregitope 治疗的效果。在 DO11.10 小鼠中用 Tregitope 处理后，观察到 KJ1-26 染色的 OVA 特异性 CD4(+)T 细胞中 FoxP3 的上调，同时抗 OVA Ig 和 T 效应器反应减少。在人类 T 细胞的体外研究中，外周血单核细胞（PBMC）对 GAD65 表位的反应在 Tregitope 的存在和不存在情况下是可变的。在使用新诊断的糖尿病患者的 PBMC 进行的体外试验中，Tregitope 对 GAD65 表位的免疫反应的抑制作用似乎更为有效，而对于其他更成熟的糖尿病患者则不然，并且抑制程度与预测的 Tregitope 的 HLA 限制的相关性得到了证实。这些定义明确的调节性 T 细胞表位的实施可能会导致 1 型糖尿病和其他自身免疫性疾病的治疗范式发生转变。
