Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Transpl Infect Dis. 2021 Aug;23(4):e13655. doi: 10.1111/tid.13655. Epub 2021 Jun 22.
Tacrolimus is widely used to prevent graft rejection after allogeneic transplantation by suppressing T cells in a non-antigen-specific fashion. Global T-cell suppression makes transplant recipients more susceptible to infection, especially infection by opportunistic intracellular pathogens. Infection followed by secondary challenge with the opportunistic intracellular bacterial pathogen, Listeria monocytogenes, was used to probe when tacrolimus most significantly impacts antimicrobial host defense. Tacrolimus-treated mice showed no difference in innate susceptibility following primary infection, whereas susceptibility to secondary challenge was significantly increased. Modifying the timing of tacrolimus initiation with respect to primary infection compared with secondary challenge showed significantly reduced susceptibility in tacrolimus-treated mice where tacrolimus was discontinued prior to secondary challenge. Thus, tacrolimus overrides protection against secondary infection primed by primary infection (and presumably live attenuated vaccines), with the most critical window for tacrolimus-induced infection susceptibility being exposure immediately prior to secondary challenge. These results have important implications for strategies designed to boost antimicrobial T-cell-mediated immunity in transplant recipients.
他克莫司通过非抗原特异性方式抑制 T 细胞，广泛用于预防同种异体移植后的移植物排斥反应。全球 T 细胞抑制使移植受者更容易感染，特别是机会性细胞内病原体的感染。感染随后用机会性细胞内细菌病原体李斯特菌进行二次攻击，用于探测他克莫司对抗菌宿主防御的影响最大的时间。在初次感染后，他克莫司治疗的小鼠在先天易感性方面没有差异，而二次攻击的易感性显著增加。与二次攻击相比，相对于初次感染调整他克莫司起始时间的修饰显示，在二次攻击前停止他克莫司治疗的小鼠中，易感性显著降低。因此，他克莫司会破坏由初次感染（和推测的活减毒疫苗）引发的针对二次感染的保护作用，他克莫司诱导感染易感性的最关键窗口是在二次攻击之前的暴露。这些结果对旨在增强移植受者抗微生物 T 细胞介导免疫的策略具有重要意义。
