Scroggins Sabrina M, Olivier Alicia K, Meyerholz David K, Schlueter Annette J
Interdisciplinary Graduate Program in Immunology, University of Iowa Graduate College, Iowa City, Iowa, United States of America ; Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa, United States of America.
PLoS One. 2013 Sep 10;8(9):e75158. doi: 10.1371/journal.pone.0075158. eCollection 2013.
Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3-4 months) and older (14-18 months) DCreg were generated using GM-CSF, IL-10, and TGFβ. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c→C57Bl/6 model of GVHD; on day 2 post-BMT (d +2), mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died), there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival) compared to young DCreg-treated BMT mice (90% survival). To investigate differences between dendritic cells (DC) in young and older DCreg-treated BMT mice that may play a role in DCreg function in vivo, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and donor DC may utilize to induce and maintain tolerance to GVHD.
尽管人类白细胞抗原匹配和药物预防有所改善，但急性移植物抗宿主病（GVHD）仍是造血干细胞移植（HSCT）后常见的致命并发症。与年轻受者相比，老年HSCT受者的发病率和死亡率显著增加。在年轻的骨髓移植（BMT）小鼠中，用同基因调节性树突状细胞（DCreg）进行预防已被证明可降低与GVHD相关的死亡率。为了评估这种方法在老年BMT受者中的效果，使用GM-CSF、IL-10和TGFβ生成了年轻（3-4个月）和老年（14-18个月）的DCreg。培养后对年轻和老年DCreg进行分析，发现其表型无差异。在BALB/c→C57Bl/6 GVHD模型中评估了DCreg治疗对老年BMT小鼠的疗效；在BMT后第2天（d +2），小鼠接受同基因、年龄匹配的DCreg。尽管与未治疗的BMT小鼠（全部死亡）相比，接受老年DCreg治疗的BMT小鼠的发病率和死亡率有所降低，但与接受年轻DCreg治疗的BMT小鼠（90%存活）相比，接受老年DCreg治疗的BMT小鼠的存活率有小幅但显著的下降（75%存活）。为了研究年轻和老年DCreg治疗的BMT小鼠中树突状细胞（DC）之间可能在体内DCreg功能中起作用的差异，在DCreg过继转移后评估了DC表型。在d +3时，在接受老年DCreg治疗的BMT小鼠中鉴定出的转移DCreg与接受年轻DCreg治疗的BMT小鼠中的DCreg相比，PD-L1和PIR B的表达显著降低。此外，与d +3相比，在接受DCreg治疗的BMT小鼠d +21时鉴定出的供体DC显示抑制性分子表达增加，共刺激分子表达降低，这表明供体DC上诱导了调节性表型。总之，这些数据表明DCreg治疗在调节老年BMT受者的GVHD方面是有效的，并为DCreg和供体DC可能用于诱导和维持对GVHD耐受性的抑制途径提供了证据。
