Inhibition of transplantation tolerance by immune senescence is reversed by endocrine modulation.
Inhibition of transplantation tolerance by immune senescence is reversed by endocrine modulation.
复制标题
DOI：
10.1126/scitranslmed.3002270
复制
发表时间：
2011-06-15
影响因子：
17.1
通讯作者：
Deng S
中科院分区：
文献类型：
--
作者：
Zhao G;Moore DJ;Kim JI;Lee KM;O'Connor MR;Duff PE;Yang M;Lei J;Markmann JF;Deng S
衰老的免疫系统对新的刺激反应不佳；胸腺退化、记忆细胞对其他特异性的积累以及对抗原信号的普遍耐受性都可能导致对感染的抵抗力较差。这些相同的变化可能会对器官移植构成重大的临床障碍，因为移植耐受需要胸腺的参与和对新抗原的整合、促进耐受的反应。我们发现，在12月龄后，小鼠对抗CD45RB的单抗治疗的耐受诱导能力产生了抵抗力。这种对同种异体心脏移植物的耐受性可以通过对雄性小鼠进行手术去势来克服，这一过程导致了胸腺再生和长期的移植物接受。Lupron Depot注射暂时扰乱性腺功能，恢复老年小鼠的耐受性，证实了这种内分泌-免疫相互作用临床转化的潜力。此外，我们证明，手术或化学去势后耐受性的恢复依赖于胸腺调节性T细胞(Treg)的产生；胸腺切除或Treg耗竭可消除耐受性的恢复。免疫系统的老化(“免疫衰老”)是免疫耐受的重要障碍，但这一障碍可以通过临床常用疗法靶向性类固醇的产生来克服。
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.
登录
查看更多内容
影响因子：
4.6
作者：
Gregg, R;Smith, CM;Moss, PA
通讯作者：
Moss, PA
DOI：
10.1073/pnas.95.7.3821
发表时间：
1998-03-31
影响因子：
11.1
作者：
Basadonna, GP;Auersvald, L;Rothstein, DM
通讯作者：
Rothstein, DM
影响因子：
4.4
作者：
Deng, Shaoping;Moore, Daniel J.;Markmann, James F.
通讯作者：
Markmann, James F.
影响因子：
3.7
作者：
Herndier-Brandstetter, Dietmar;Veel, Ellen;Grubeck-Loebenstein, Beatrix
通讯作者：
Grubeck-Loebenstein, Beatrix
影响因子：
158.5
作者：
Belshe, RB;Newman, FK;Dubin, G
通讯作者：
Dubin, G