Zeiser Robert, Nguyen Vu H, Beilhack Andreas, Buess Martin, Schulz Stephan, Baker Jeanette, Contag Christopher H, Negrin Robert S
Center for Clinical Science Research, Division of Bone Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Blood. 2006 Jul 1;108(1):390-9. doi: 10.1182/blood-2006-01-0329. Epub 2006 Mar 7.
CD4+CD25+ regulatory T (Treg) cells control immunologic tolerance and antitumor immune responses. Therefore, in vivo modification of Treg function by immunosuppressant drugs has broad implications for transplantation biology, autoimmunity, and vaccination strategies. In vivo bioluminescence imaging demonstrated reduced early proliferation of donor-derived luciferase-labeled conventional T cells in animals treated with Treg cells after major histocompatibility complex mismatch bone marrow transplantation. Combining Treg cells with cyclosporine A (CSA), but not rapamycin (RAPA) or mycophenolate mofetil (MMF), suppressed Treg function assessed by increased T-cell proliferation, graft-versus-host disease (GVHD) severity, and reduced survival. Expansion of Treg and FoxP3 expression within this population was lowest in conjunction with CSA, suggesting that calcineurin-dependent interleukin 2 (IL-2) production is critically required for Treg cells in vivo. The functional defect of Treg cells after CSA exposure could be reversed by exogenous IL-2. Further, the Treg plus RAPA combination preserved graft-versus-tumor (GVT) effector function against leukemia cells. Our data indicate that RAPA and MMF rather than CSA preserve function of Treg cells in pathologic immune responses such as GVHD without weakening the GVT effect.
CD4+CD25+调节性T（Treg）细胞控制免疫耐受和抗肿瘤免疫反应。因此，免疫抑制药物对Treg功能进行体内修饰，对移植生物学、自身免疫和疫苗接种策略具有广泛影响。体内生物发光成像显示，在主要组织相容性复合体不匹配的骨髓移植后，用Treg细胞处理的动物中，供体来源的荧光素酶标记的传统T细胞早期增殖减少。将Treg细胞与环孢素A（CSA）联合使用，但不与雷帕霉素（RAPA）或霉酚酸酯（MMF）联合使用，通过增加T细胞增殖、移植物抗宿主病（GVHD）严重程度和降低生存率来评估，可抑制Treg功能。在该群体中，Treg和FoxP3表达的扩增与CSA联合时最低，表明钙调神经磷酸酶依赖性白细胞介素2（IL-2）的产生在体内对Treg细胞至关重要。CSA暴露后Treg细胞的功能缺陷可通过外源性IL-2逆转。此外，Treg加RAPA组合保留了针对白血病细胞的移植物抗肿瘤（GVT）效应功能。我们的数据表明，在GVHD等病理性免疫反应中，RAPA和MMF而非CSA保留了Treg细胞的功能，而不会削弱GVT效应。
