Noyan F, Lee Y-S, Hardtke-Wolenski M, Knoefel A-K, Taubert R, Baron U, Manns M P, Jaeckel E
Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany.
Transplant Proc. 2013 Jun;45(5):1832-7. doi: 10.1016/j.transproceed.2013.01.073.
CD4(+)CD25highFOXP3(+) regulatory T cells (Tregs) can control allospecific immune responses in vitro and in titrated lymphopenic transplantation models. However, under non-lymphopenic conditions, as seen in patients with autoimmune diseases or after organ transplantation, polyspecific Tregs so far have been largely ineffective to control immune responses in animal models. Yet currently polyspecific CD4(+)CD25high Tregs are being tested in clinical trials. Donor materials are usually limited for the generation of donor-specific Tregs. Herein we have developed a method to produce large quantities of activated donor B cells by stimulation of donor peripheral blood mononuclear cells with 3T3 fibroblasts expressing CD40L. These activated donor B cells are potent stimulators of CD4(+)CD25high Tregs, which were expanded efficiently to inhibit an allo-MLR in donor-specific fashion. They were far more potent in inhibiting alloimmune responses in humanized mice compared with the polyspecific CD4(+)CD25high Tregs. Generation of donor-specific Tregs could be performed under good manufacturing practice conditions. Donor-reactive Tregs may be a valuable tool to control immune responses after transplantation a setting in which polyspecific Tregs have failed to date.
CD4(+)CD25highFOXP3(+)调节性T细胞（Tregs）可在体外以及在经过滴定的淋巴细胞减少的移植模型中控制同种异体特异性免疫反应。然而，在非淋巴细胞减少的条件下，如在自身免疫性疾病患者或器官移植后的患者中所见，到目前为止，多特异性Tregs在动物模型中很大程度上无法有效控制免疫反应。然而目前多特异性CD4(+)CD25high Tregs正在临床试验中接受测试。用于产生供体特异性Tregs的供体材料通常有限。在此，我们开发了一种方法，通过用表达CD40L的3T3成纤维细胞刺激供体外周血单个核细胞来大量产生活化的供体B细胞。这些活化的供体B细胞是CD4(+)CD25high Tregs的有效刺激物，其被有效扩增以以供体特异性方式抑制同种异体混合淋巴细胞反应（allo-MLR）。与多特异性CD4(+)CD25high Tregs相比，它们在抑制人源化小鼠的同种异体免疫反应方面效力更强。供体特异性Tregs的产生可在良好生产规范条件下进行。供体反应性Tregs可能是一种有价值的工具，用于控制移植后免疫反应，而在这种情况下多特异性Tregs迄今为止已告失败。
