Wang Xiao-Nong, Haniffa Muzlifah A, Holtick Udo, Collin Matthew P, Jackson Graham, Hilkens Catharien M U, Holler Ernst, Edinger Matthias, Hoffmann Petra, Dickinson Anne M
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom.
Transplantation. 2009 Jul 27;88(2):188-97. doi: 10.1097/TP.0b013e3181ac14ce.
Despite the promising therapeutic potential of regulatory T cells (Treg) in animal studies of graft-versus-host disease (GVHD), little is known about their effect on human GVHD. Whether Treg are capable of ameliorating GVHD tissue damage has never been demonstrated in humans. It is also unknown whether Treg modulation of GVH histopathologic damage relies on their presence during effector T-cell priming, or whether allogeneic Treg are safe to use clinically.
To address these questions, we used an in vitro human skin explant GVHD model, which mimics the physiopathology of GVHD. First, "donor"-derived CD8 T cells were stimulated with human leukocyte antigen-unmatched "recipient" dendritic cells (priming phase), then primed "donor" CD8 T cells were co-cultured with "recipient" skin to induce GVH tissue damage (effector phase). "Donor"-derived Treg were added at the priming or effector phase of the GVH response. Histopathologic changes in the skin were evaluated using a clinically validated GVHD scoring system.
"Donor"-derived Treg significantly reduced the severity of GVH histopathologic damage when present during T-cell priming. In contrast, Treg failed to prevent GVH tissue damage when added to the skin co-culture (effector phase), concurrently with primed T cells. Importantly, "donor" Treg alone did not induce GVH tissue damage. Delayed Treg addition led to reduced and impaired Treg suppression of CD8 T-cell activation and their cytolytic function.
"Donor"-derived Treg effectively suppress CD8 T-cell-mediated GVH tissue damage but are critically required during priming of effector T cells. "Donor"-derived Treg seem to be safe and do not induce GVH histopathologic damage.
尽管调节性T细胞（Treg）在移植物抗宿主病（GVHD）动物研究中具有潜在的治疗前景，但对其在人类GVHD中的作用了解甚少。Treg是否能够改善GVHD组织损伤在人类中尚未得到证实。同样未知的是，Treg对GVH组织病理学损伤的调节作用是依赖于效应T细胞启动阶段它们的存在，还是同种异体Treg在临床上使用是安全的。
为了解决这些问题，我们使用了一种体外人皮肤外植体GVHD模型，该模型模拟了GVHD的生理病理学。首先，用与人类白细胞抗原不匹配的“受体”树突状细胞刺激“供体”来源的CD8 T细胞（启动阶段），然后将启动后的“供体”CD8 T细胞与“受体”皮肤共培养以诱导GVH组织损伤（效应阶段）。在GVH反应的启动或效应阶段添加“供体”来源的Treg。使用经过临床验证的GVHD评分系统评估皮肤的组织病理学变化。
当在T细胞启动阶段存在时，“供体”来源的Treg显著降低了GVH组织病理学损伤的严重程度。相比之下，当在皮肤共培养（效应阶段）中与启动后的T细胞同时添加Treg时，Treg未能预防GVH组织损伤。重要的是，单独的“供体”Treg不会诱导GVH组织损伤。延迟添加Treg会导致Treg对CD8 T细胞活化及其细胞溶解功能的抑制作用减弱和受损。
“供体”来源的Treg可有效抑制CD8 T细胞介导的GVH组织损伤，但在效应T细胞启动阶段至关重要。“供体”来源的Treg似乎是安全的，不会诱导GVH组织病理学损伤。
