性激素修饰胸腺重构联合同种异基因骨髓移植促进中枢性免疫耐受的功能与机制研究

The intact function of thymus is closely related to the successful induction of transplant tolerance, but the thymus gradually shrinks and the function decreases after adolescence. Our previous study found that anti-CD45RB antibody could not induce immune tolerance in aged mice with thymus atrophy. However, the regeneration of thymus could be made by surgical or chemical castration (sex hormone modulation), hence, restoring the induction ability by the antibody. With the discovery of chimerism after bone marrow transplantation, the establishment of mixed chimeric tolerance in the way of thymus has become a hot topic. However, vast majority of literature focused on the subject of young animals, and few aimed at the immune tolerance induction by bone marrow stem cell transplantation in aged animals, In this study, we used allograft skin transplantation model in 16-month-old mouse, which was transplanted allogeneic bone marrow intravenously or injected with bone marrow cells directly into thymus to observe the immune response to the graft. Further, the thymic regeneration was made through the chemical castration to observe whether it can promote the ability of immune tolerance induction by bone marrow transplantation. Moreover, the tolerance mechanism involved was explored. With the advent of the aging society in China, the elucidation of these problems will help to succeed in organ transplantation for the elderly population and provide new thinking and treatment strategies for certain autoimmune diseases.

健全的胸腺功能与移植免疫耐受的成功诱导密切相关。前期研究发现，随着青春期后胸腺逐渐萎缩，功能下降，抗CD45RB抗体无法诱导老龄胸腺萎缩小鼠对移植物的免疫耐受，但通过外科或化学去势方法抑制性激素（性激素修饰），可使胸腺再生重构，从而恢复耐受诱导能力。随着骨髓移植嵌合现象的发现，通过胸腺建立混合嵌合状态诱导耐受已成为研究的热点，但绝大多数文献研究对象为年轻动物，而骨髓干细胞移植对老龄动物免疫耐受的诱导能力，文献报道很少。本研究拟采用16月龄老龄小鼠同种异基因皮肤移植模型，经静脉途径同种异基因骨髓移植或经胸腺途径直接注射骨髓细胞，观察其对移植物的免疫诱导能力。进一步通过化学去势方法使胸腺再生，观察其能否促进骨髓移植对移植物的免疫耐受，并对可能的耐受机制进行研究。随着我国老龄化社会的到来，对于上述问题的探讨，有助于更能成功的为老龄人群进行器官移植及某些自身免疫疾病的治疗提供新的思维和治疗策略。

健全的胸腺功能与移植免疫耐受的成功诱导密切相关。前期研究发现，随着青春期后胸腺 逐渐萎缩，功能下降，抗CD45RB抗体无法诱导老龄胸腺萎缩小鼠对移植物的免疫耐受，但通过外科或化学去势方法抑制性激素（性激素修饰），可使胸腺再生重构，从而恢复耐受诱导能力 。随着骨髓移植嵌合现象的发现，通过胸腺建立混合嵌合状态诱导耐受已成为研究的热点，但绝大多数文献研究对象为年轻动物，而骨髓干细胞移植对老龄动物免疫耐受的诱导能力，文献报道很少。本研究拟采用16月龄老龄小鼠同种异基因皮肤移植模型，经静脉途径同种异基因骨髓移植或经胸腺途径直接注射骨髓细胞，观察其对移植物的免疫诱导能力。进一步通过化学去势方法使胸腺再生，观察其能否促进骨髓移植对移植物的免疫耐受，并对可能的耐受机制进行研究。随着我国老龄化社会的到来，对于上述问题的探讨，有助于更能成功的为老龄人群进行器官移植及某些自身免疫疾病的治疗提供新的思维和治疗策略。