mTOR Inhibitor Therapy Diminishes Circulating CD8+ CD28- Effector Memory T Cells and Improves Allograft Inflammation in Belatacept-refractory Renal Allograft Rejection

被引:15
作者
Castro-Rojas, Cyd M. [1 ]
Godarova, Alzbeta [1 ]
Shi, Tiffany [1 ]
Hummel, Sarah A. [1 ]
Shields, Adele [2 ]
Tremblay, Simon [2 ]
Alloway, Rita R. [3 ]
Jordan, Michael B. [1 ,4 ,5 ]
Woodle, E. Steve [2 ]
Hildeman, David A. [1 ,5 ]
机构
[1] Cincinnati Childrens Hosp, Div Immunobiol, Cincinnati, OH USA
[2] Univ Cincinnati, Coll Med, Dept Surg, Div Transplantat, POB 670558,231 Albert Sabin Way, Cincinnati, OH 45267 USA
[3] Univ Cincinnati, Coll Med, Dept Internal Med, Div Nephrol, Cincinnati, OH USA
[4] Cincinnati Childrens Res Fdn, Div Bone Marrow Transplant & Immune Deficiency, Cincinnati, OH USA
[5] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA
基金
美国国家卫生研究院;
关键词
KIDNEY-TRANSPLANT RECIPIENTS; RAPAMYCIN INHIBITORS; MAMMALIAN TARGET; CLINICAL-TRIAL; PHASE-III; IN-VITRO; CALCINEURIN; PROLIFERATION; TACROLIMUS; IMMUNOSUPPRESSION;
D O I
10.1097/TP.0000000000002917
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Renal allograft rejection is more frequent under belatacept-based, compared with tacrolimus-based, immunosuppression. We studied kidney transplant recipients experiencing rejection under belatacept-based early corticosteroid withdrawal following T-cell-depleting induction in a recent randomized trial (Belatacept-based Early Steroid Withdrawal Trial, NCT01729494) to determine mechanisms of rejection and treatment. Methods. Peripheral mononuclear cells, serum creatinine levels, and renal biopsies were collected from 8 patients undergoing belatacept-refractory rejection (BRR). We used flow cytometry, histology, and immunofluorescence to characterize CD8(+) effector memory T cell (T-EM) populations in the periphery and graft before and after mammalian target of rapamycin (mTOR) inhibition. Results. Here, we found that patients with BRR did not respond to standard antirejection therapy and had a substantial increase in alloreactive CD8(+) T cells with a CD28(low)/DRhi/CD38(hi)/CD45RO(+) T-EM. These cells had increased activation of the mTOR pathway, as assessed by phosphorylated ribosomal protein S6 expression. Notably, everolimus (an mTOR inhibitor) treatment of patients with BRR halted the in vivo proliferation of T-EM cells and their ex vivo alloreactivity and resulted in their significant reduction in the peripheral blood. The frequency of circulating FoxP3(+) regulatory T cells was not altered. Importantly, everolimus led to rapid resolution of rejection as confirmed by histology. Conclusions. Thus, while prior work has shown that concomitant belatacept + mTOR inhibitor therapy is effective for maintenance immunosuppression, our preliminary data suggest that everolimus may provide an available means for effecting "rescue" therapy for rejections occurring under belatacept that are refractory to traditional antirejection therapy with corticosteroids and polyclonal antilymphocyte globulin.
引用
收藏
页码:1058 / 1069
页数:12
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