Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 52662, Israel.
J Clin Immunol. 2010 Sep;30(5):659-68. doi: 10.1007/s10875-010-9430-5. Epub 2010 Jun 11.
Diabetogenic autoreactive T cells with effector/memory characteristics are described in type 1 diabetes patients (T1D). Alternatively activated dendritic cells (aaDCs) have been regarded as promising tools for clinical application in autoimmune diseases (ADs), although their ability to induce antigen-specific tolerance in T cells derived from ADs has yet to be determined.
Monocyte-derived dendritic cells (DCs) were produced utilizing GM-CSF and IL-4, and aaDCs by adding IL-10 and TGF-beta (10/TGF-DC) during differentiation. Both cell groups were insulin-loaded, maturated with lipopolysaccharide, and cocultured with autologous effector/memory T cells derived from T1D individuals, in order to evaluate the induction of insulin-specific tolerance.
In five of eight T1D patients analyzed in vitro, 10/TGF-DC were able to induce insulin-specific tolerance in effector/memory CD4+ T cells (50.4% +/- 13.2 less proliferation), without affecting the proliferative response to an unrelated antigen (candidin). Tolerance induction was dependent on the current activation state of CD4+ T cells in each patient. 10/TGF-DC-stimulated T cells acquired an IL-2(low)IFN-gamma(low)IL-10(high) cytokine profile, and their hyporesponsiveness could be reverted upon exposure to IL-2. This study shows a perspective about the in vitro ability of monocyte-derived 10/TGF-DC to induce antigen-specific tolerance in effector/memory T cells generated during the course of an autoimmune disease.
1 型糖尿病（T1D）患者体内存在具有效应/记忆特征的致糖尿病自身反应性 T 细胞。交替激活的树突状细胞（aaDC）已被认为是自身免疫性疾病（AD）临床应用的有前途的工具，尽管它们在诱导 AD 来源的 T 细胞产生抗原特异性耐受方面的能力尚未确定。
利用 GM-CSF 和 IL-4 产生单核细胞来源的树突状细胞（DC），在分化过程中加入 IL-10 和 TGF-β（10/TGF-DC）产生 aaDC。将这两组细胞负载胰岛素，用脂多糖成熟，与来自 T1D 个体的自身效应/记忆 T 细胞共培养，以评估诱导胰岛素特异性耐受的能力。
在体外分析的 8 名 T1D 患者中的 5 名中，10/TGF-DC 能够诱导效应/记忆 CD4+T 细胞的胰岛素特异性耐受（50.4%±13.2 增殖减少），而不影响对无关抗原（念珠菌）的增殖反应。耐受诱导依赖于每位患者中 CD4+T 细胞的当前激活状态。10/TGF-DC 刺激的 T 细胞获得了 IL-2(low)IFN-γ(low)IL-10(high)细胞因子谱，并且它们的低反应性可以在暴露于 IL-2 时恢复。这项研究展示了单核细胞来源的 10/TGF-DC 在体外诱导自身免疫性疾病过程中产生的效应/记忆 T 细胞产生抗原特异性耐受的能力。
