Goldberg Gabrielle L, Alpdogan Onder, Muriglan Stephanie J, Hammett Maree V, Milton Morag K, Eng Jeffrey M, Hubbard Vanessa M, Kochman Adam, Willis Lucy M, Greenberg Andrew S, Tjoe Kartono H, Sutherland Jayne S, Chidgey Ann, van den Brink Marcel R M, Boyd Richard L
Department of Pathology and Immunology, Central and Eastern Clinical School, Monash University, Melbourne, Australia.
J Immunol. 2007 Jun 1;178(11):7473-84. doi: 10.4049/jimmunol.178.11.7473.
Delayed immune reconstitution in adult recipients of allogeneic hemopoietic stem cell transplantations (HSCT) is related to age-induced thymic atrophy. Overcoming this paucity of T cell function is a major goal of clinical research but in the context of allogeneic transplants, any strategy must not exacerbate graft-vs-host disease (GVHD) yet ideally retain graft-vs-tumor (GVT) effects. We have shown sex steroid ablation reverses thymic atrophy and enhances T cell recovery in aged animals and in congenic bone marrow (BM) transplant but the latter does not have the complications of allogeneic T cell reactivity. We have examined whether sex steroid ablation promoted hemopoietic and T cell recovery following allogeneic HSCT and whether this benefit was negated by enhanced GVHD. BM and thymic cell numbers were significantly increased at 14 and 28 days after HSCT in castrated mice compared with sham-castrated controls. In the thymus, the numbers of donor-derived thymocytes and dendritic cells were significantly increased after HSCT and castration; donor-derived BM precursors and developing B cells were also significantly increased. Importantly, despite restoring T cell function, sex steroid inhibition did not exacerbate the development of GVHD or ameliorate GVT activity. Finally, IL-7 treatment in combination with castration had an additive effect on thymic cellularity following HSCT. These results indicate that sex steroid ablation can profoundly enhance thymic and hemopoietic recovery following allogeneic HSCT without increasing GVHD and maintaining GVT.
异基因造血干细胞移植（HSCT）成年受者的免疫重建延迟与年龄相关的胸腺萎缩有关。克服T细胞功能的这种不足是临床研究的主要目标，但在异基因移植的背景下，任何策略都不能加重移植物抗宿主病（GVHD），同时理想情况下要保留移植物抗肿瘤（GVT）效应。我们已经表明，性类固醇消融可逆转老年动物和同基因骨髓（BM）移植中的胸腺萎缩并增强T细胞恢复，但后者没有异基因T细胞反应性的并发症。我们研究了性类固醇消融是否能促进异基因HSCT后的造血和T细胞恢复，以及这种益处是否会因GVHD增强而被抵消。与假阉割对照组相比，阉割小鼠在HSCT后14天和28天的BM和胸腺细胞数量显著增加。在胸腺中，HSCT和阉割后供体来源胸腺细胞和树突状细胞的数量显著增加；供体来源的BM前体细胞和发育中的B细胞也显著增加。重要的是，尽管恢复了T细胞功能，但性类固醇抑制并未加重GVHD的发展或改善GVT活性。最后，IL-7治疗与阉割联合对HSCT后的胸腺细胞数量有相加作用。这些结果表明，性类固醇消融可在不增加GVHD并维持GVT的情况下，显著增强异基因HSCT后的胸腺和造血恢复。
