Coenen J J A, Koenen H J P M, van Rijssen E, Kasran A, Boon L, Hilbrands L B, Joosten I
Department of Bloodtransfusion and Transplantation Immunology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Bone Marrow Transplant. 2007 May;39(9):537-45. doi: 10.1038/sj.bmt.1705628. Epub 2007 Mar 12.
Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3(+) regulatory T-cell (T(REG)) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for T(REG) homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on T(REG) homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4(+)CD25(+)FoxP3(+) T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25(+)FoxP3(+) T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4(+)FoxP3(+) T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4(+)FoxP3(+) T(REG) in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.
移植物抗宿主病（GVHD）是异基因干细胞移植（SCT）后预后不良的最常见原因。最近，利用FOXP3（+）调节性T细胞（T（REG））功能正成为一种有前景的策略，可在保留移植物抗白血病（GVL）作用的同时抑制GVHD。环孢素和雷帕霉素通过阻断白细胞介素（IL）-2来减少效应T细胞的扩增，但IL-2信号传导对于T（REG）的稳态至关重要。GVHD的解决严重依赖于免疫调节系统的胸腺依赖性重建。因此，人们一直担心免疫抑制剂阻断IL-2信号传导对T（REG）稳态的影响。在此，我们在小鼠模型中证明，与雷帕霉素不同，环孢素不仅损害胸腺中CD4（+）CD25（+）FoxP3（+）T细胞的生成，还损害它们在外周免疫区室中的稳态行为。用环孢素治疗导致所研究的所有免疫区室中外周CD25（+）FoxP3（+）T细胞急剧减少。长期使用雷帕霉素治疗可使胸腺生成CD4（+）FoxP3（+）T细胞，而用环孢素治疗则导致这些细胞生成减少。总之，环孢素和雷帕霉素在体内对CD4（+）FoxP3（+）T（REG）的稳态有不同影响。由于外周耐受诱导是异基因SCT后成功治疗结果的先决条件，这些发现具有潜在的临床意义。
