摘要：一项在小鼠身上进行的新的研究报告说，抑制性激素产生的药物可帮助诱导老年人对移植物的免疫耐受性。 这些发现指出了一种确保移植成功的新的基于激素的疗法。 人们常常将青少年的不稳定的行为归咎于其体内的“狂暴的激素”；但激素水平的差异则不能够解释老年人中发生的变化。 例如，老年人的免疫系统常常对移植器官反应不良，使得他们易于感染而且难以达到对移植器官的免疫耐受状态。 研究人员认为，这种障碍的部分原因是老年人的胸腺发生萎缩，而胸腺是机体产生免疫系统T细胞的主要器官。 胸腺萎缩常常始于青春期，那时人体的性激素水平开始快速地变化。 Gaoping Zhao及其同事如今显示，通过给老迈小鼠做外科去势手术来改变性激素的水平可逆转其胸腺的萎缩，并提高身体对移植物的免疫耐受。 明确地说，该研究团队发现，在对心脏移植努力产生免疫耐受的老迈小鼠中，对其进行去势手术可导致其机体长期地接受移植物并恢复胸腺细胞的产生。 接下来，研究人员以一种病人更能接受的方法证实了他们的发现：用一种化疗药物（叫做储库型醋酸亮丙瑞林）来化学性地操纵性激素。 该药物是通过暂时性地破坏男性的性腺功能而起作用的，它被用来治疗前列腺癌。 研究人员在给小鼠注射了储库型醋酸亮丙瑞林之后看到了类似的诱导移植物耐受的效应。 尽管很难比较小鼠和人的年龄，这些结果提示，激素修饰也许可在老年人中改善其对移植物的接受性。
生物探索推荐英文原文：
Get rid of sex hormones, boost organ transplant tolerance
Drugs that suppress the production of sex hormones could help induce transplant tolerance in elderly patients, reports a new study in mice. The findings point toward a new hormone-based therapy to ensure successful transplants. “Raging hormones” are often blamed for the erratic behavior of teenagers; but hormonal differences aren’t given the credit they deserve for changes in older adults. For example, older immune systems often respond poorly to organ transplants, setting the stage for infections and difficulty achieving tolerance. Researchers believe this failure may be due in part to the shrinking of the thymus, the main producer of immune T cells. Thymus shrinkage often begins at the onset of puberty, when sex hormone levels start to change rapidly. Gaoping Zhao and colleagues now show that modifying sex hormone levels by surgically castrating aged mice can reverse thymus atrophy and boost transplant tolerance. Specifically, in elderly mice struggling to develop tolerance to cardiac transplants, surgical castration led to long-term graft acceptance and restoration of thymus cells, the team found. Next, the researchers confirmed their findings with a more patient-friendly procedure: chemical manipulation of sex hormones with a chemotherapy drug called lupron depot. The drug works by temporarily disrupting gonad function in men, and is used to treat prostate cancer. The researchers saw similar transplant tolerance-inducing effects after injecting lupron depot into mice. Although it is difficult to compare mouse years to human years, the results suggest that hormone modification may improve transplant acceptance in older adult humans.
生物探索推荐英文论文摘要：
Sci Transl Med 15 June 2011:
Vol. 3, Issue 87, p. 87ra52
DOI: 10.1126/scitranslmed.3002270
TRANSPLANTATION TOLERANCE--Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation
ABSTRACT
The senescent immune system responds poorly to new stimuli; thymic involution, accumulation of memory cells against other specificities, and general refractoriness to antigen signaling all may contribute to poor resistance to infection. These same changes may pose a significant clinical barrier to organ transplantation, as transplantation tolerance requires thymic participation and integrated, tolerance-promoting responses to novel antigens. We found that after the age of 12 months, mice became resistant to the tolerance-inducing capacity of the monoclonal antibody therapy anti-CD45RB. This resistance to tolerance to cardiac allografts could be overcome by surgical castration of male mice, a procedure that led to thymic regeneration and long-term graft acceptance. The potential for clinical translation of this endocrine-immune interplay was confirmed by the ability of Lupron Depot injections, which temporarily disrupt gonadal function, to restore tolerance in aged mice. Furthermore, we demonstrated that the restoration of tolerance after surgical or chemical castration depended on thymic production of regulatory T cells (Tregs); thymectomy or Treg depletion abrogated tolerance restoration. The aging of the immune system (“immune senescence”) is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics.
