Scalea Joseph R, Torabi Radbeh, Tena Aseda, Tasaki Masayuki, Gillon Bradford C, Moran Shannon, Cormack Taylor, Villani Vincenzo, Shimizu Akira, Sachs David H, Yamada Kazuhiko
Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, United States; Harvard Medical School, Boston, MA 02129, United States.
Transpl Immunol. 2014 Sep;31(3):134-9. doi: 10.1016/j.trim.2014.09.001. Epub 2014 Sep 18.
We have previously demonstrated that the juvenile thymus plays an essential role in tolerance induced by both renal transplantation and a short course of calcineurin inhibitors. Aged thymi have a decreased ability to induce tolerance. Luteinizing hormone-releasing hormone (LHRH) is known to pharmacologically rejuvenate the thymus in rodents. In order to develop a clinically applicable regimen of transplantation tolerance in adults, we sought to determine if thymic rejuvenation would occur with LHRH agonism in non-human primates.
Thymic rejuvenation was evaluated by magnetic resonance imaging (MRI), histology, as well as in-vitro cellular and molecular tests. Four aged male hamadryas baboons underwent subcutaneous injection of a 3-month depot of Lupron (11.25mg; LI) and were followed for 3 months. Thymi increased volumetrically by MRI. After LI, thymic cellularity markedly increased within the cortical and medullary thymus. Additionally, a significant increase in the CD4(+)/CD45RA(hi+) population in the peripheral blood occurred for 50 days after LI, and flow cytometry of thymic tissue revealed a large increase in the percentage of CD4(+)/CD8(+) cells. TREC assay corroborated enhancement in thymic function.
These data indicate that LI is associated with thymic rejuvenation in baboons, and further confirm that extrinsic factors play an important role in thymic rejuvenation in a non-human primate model.
我们之前已经证明，幼年胸腺在肾移植和短期使用钙调神经磷酸酶抑制剂诱导的免疫耐受中起关键作用。老年胸腺诱导免疫耐受的能力下降。已知促黄体生成素释放激素（LHRH）在药理学上可使啮齿动物的胸腺恢复活力。为了开发一种临床上适用于成人的移植耐受方案，我们试图确定在非人灵长类动物中，LHRH激动剂是否会使胸腺恢复活力。
通过磁共振成像（MRI）、组织学以及体外细胞和分子检测来评估胸腺恢复活力情况。对4只老年雄性阿拉伯狒狒皮下注射3个月长效的抑那通（11.25mg；LI），并随访3个月。通过MRI检测发现胸腺体积增大。注射LI后，皮质和髓质胸腺内的细胞数量明显增加。此外，注射LI后50天外周血中CD4(+)/CD45RA(hi+)细胞群显著增加，胸腺组织的流式细胞术显示CD4(+)/CD8(+)细胞百分比大幅增加。TREC检测证实胸腺功能增强。
这些数据表明，LI与狒狒的胸腺恢复活力有关，并进一步证实外在因素在非人灵长类动物模型的胸腺恢复活力中起重要作用。
