西罗莫司
过继性细胞移植
FOXP3型
体内
白细胞介素2受体
免疫学
移植
医学
抗胸腺细胞球蛋白
体外
T细胞
生物
免疫系统
球蛋白
内科学
生物化学
生物技术
作者
Anlun Ma,Shijie Qi,Lijun Song,Yanxin Hu,Hao Dun,Eric M. Massicotte,Martine Dupuis,Pierre Daloze,Huifang Chen
标识
DOI:10.1016/j.intimp.2010.11.001
摘要
Although donor alloantigen specific Treg cells play an important role in transplant tolerance, therapeutic applications are limited by their low frequency. In this study, isolated Tregs from Cynomolgus monkeys were efficiently expanded by a co-culture system, and maintained suppressive function on the proliferation of CD4+ effector cells in vitro. Adoptive transfer of expanded donor alloantigen specific Tregs without any immunosuppressants could prolong survival of MHC-mismatched allografts in Cynomolgus monkeys. To reach the feasibility of clinical transplantation, our objectives focused on whether exposure of monkey Tregs to immunosuppressants could preserve suppressive function in vitro and in vivo. The results showed that low-dose sirolimus selectively expanded Tregs, increased the expression of CD25bright and Foxp3 markers, and suppressed TCR- or allo-antigens induced CD4+ T cell proliferation in vitro. In vivo, after pre-treated with anti-thymocyte globulin (ATG) for consecutive 3 days, a 14-day therapy of adoptive infusion of donor alloantigen-specific Tregs combined with low-dose sirolimus delayed acute rejection of renal allografts in Cynomolgus monkeys, showing an MST of 48.5 days as compared with those of untreated and sirolimus-treated monkeys (7 days and 22 days). The frequencies of CD4+CD25bright T cells were significantly elevated in mesenteric lymph nodes vs. those in inguino lymph nodes and peripheral blood. In summary, expanded donor alloantigen specific Tregs exposed to sirolimus can preserve inhibition in vitro and in vivo. Tregs are more resistant to sirolimus than other T cells. Expanded donor alloantigen specific Tregs combined with sirolimus and ATG prolongs renal allograft survival in monkeys, suggesting that sirolimus might be one of the best synergists for Tregs therapy.
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