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제목	Effect of inflammation on intracellular concentration of tacrolimus.
저자	Eunjin Bae*, Seung Hee Yang, Yon Su Kim
출판정보	2016; 2016(1):
키워드	None
초록	Background: Calcineurin inhibitors improved the prognosis of transplant recipients. It is difficult to keep balance between immunosuppression and minimization of infection risk using calcineurin inhibitos. CNI is the substrate of ABCB1, which transports drugs from the intracellular to the extracellular domain. ABCB1 expression and function are controlled by hyaluronic acid (HA) and the HA receptor CD44. We evaluated the effect of inflammation on intracellular concentration of tacrolimus, specifically, its associations between ABCB1 and CD44. Methods: We prospectively enrolled 9 kidney recipients with AR between April 2015 and January 2016. We measured both whole blood and intracellular concentration of tacrolimus (BC-TAC and IC-TAC) in 9 kidney recipients with AR and stable status. IC-TAC were measured using LC-MS/MS. The tacrolimus ratio was defined as the ratio between IC-TAC and BC-TAC (IC-TAC/BC-TAC). A human T lymphoblastoid cell line (Jurkat T cell line) was treated with tacrolimus by dose dependent manners for 21 hours and stimulated with PMA/ionomycin for 3hours. IC-TAC was measured with and without tacrolimus, PMA/ionomycin. The effect of tacrolimus on cell proliferation were measured by MTS assay. Interlieukin-2, 8 and interferon gamma production were measured by RT-PCR. Furthermore, we analyzed the expression of CD44+ and ABCB1+ cells by FACS to examine the change of IC-TAC respect to treated tacolimus level and stimulation. Results: In human data, only one person’s TAC-ratio was lower at the time of AR than that of stable status. The other patients’ TAC-ratio were higher at inflammatory status (infection: n=3, rejection: n=5) than stable status. The person who had lower level of TAC-ratio at the time of AR experienced recurrent inflammatory conditions, pneumonia and acute rejection, during 1month. Other patients did not experience an inflammatory conditions at least 6 months before this event (AR or infection). In vitro data, the levels of IC-TAC increase proportionally with the levels of treated tacrolimus in Jurkat T cells (figure 1). After stimulation with PMA/ionomycin, the proportion of T cells producing IFN-γ, IL-2 and 8 was higher in the 0, 2.5 ng/ml tacrolimus treated groups than the 5ng/ml tacrolimus treated group. In addition, the levels of IC-TAC were decreased after stimulation. Under the same conditions, the frequency of CD44+ABCB1+ cells were increased with tacrolimus treatment and stimulation in FACS. Conclusion: This study supports a hypothesis that chronic or recurrent inflammation such as rejection, infection, can decrease the intracellular tacrolimus level. This could be explained by drug efflux function of CD44+ABCB1+ cells. Further studies must be warranted to explain the difference between human data and in-vivo study. Figures:
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