Calcineurin inhibitors (CNIs) and corticosteroids (CSS) have substantial untoward side effects, most notably nephrotoxicity. Consequently, the FDA approved belatacept for maintenance immunosuppression. We recently completed enrollment for a multi-center randomized clinical trial investigating the role of belatacept-based early steroid withdrawal under T cell-depleting induction therapy in kidney transplant recipients (BEST Trial, clinicaltrials.gov #NCT01729494). Compared to tacrolimus, the number of rejections episodes were higher, greater in histologic severity and less responsive to standard antirejection therapy, thereby indicating that they were clinically and immunologically distinct from those that occur under CNI-based therapy. Importantly, the mechanism(s) that mediate rejection under belatacept therapy remain to be defined.

We found that patients undergoing belatacept resistant acute rejection have an expansion of alloreactive T cells with a CD28<sup style="font-family: Arial, sans-serif;">lo/DR<sup style="font-family: Arial, sans-serif;">hi/CD38hi/CD45RO<sup style="font-family: Arial, sans-serif;">+phenotype (T<sub style="font-family: Arial, sans-serif;">EM). Treatment of these patients with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, causes substantial loss of peripheral blood T<sub style="font-family: Arial, sans-serif;">EM CD8+, but not FoxP3+ regulatory T cells that is associated with clinical/histologic control of the rejection process. Additionally, everolimus treatment led to a preferential loss of CD40L on activated T<sub style="font-family: Arial, sans-serif;">EM CD8+ T cells. Moreover, preliminary data suggest differential expression of CD40L on alloreactive T cells from tacrolimus versus belatacept-treated patients. Ongoing studies are examining the donor-specific alloreactivity and gene signatures of T<sub style="font-family: Arial, sans-serif;">EM CD8+ T cells as well as the effects of belatacept and mTOR inhibition on CD40L expression.

CITATION INFORMATION: Castro Rojas C., Godarova A., Rike Shields A., Alloway R., Jordan M., Woodle E., Hildeman D. Belatacept-Refractory CD8⁺CD28^–CD38^hi Effector/Memory T Cells Are Targeted by mTOR Inhibition Leading to a Preferential Loss of CD40L Am J Transplant. 2017;17 (suppl 3).

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