Bortezomib can suppress activation of rapamycin-resistant memory T cells without affecting regulatory T-cell viability in non-human primates

BACKGROUND: Memory T cells specific for donor antigens are currently recognized as a significant barrier for maintaining a successful transplant. Furthermore, it has been shown that commonly used immunosuppressive drugs do not alleviate this memory response. Here, we report that rapamycin allows significant proliferation of memory T cells and bortezomib can abrogate the proliferation of rapamycin-resistant memory T cells when preserving the survival of regulatory T cells. METHODS: Peripheral blood mononuclear cells freshly isolated from non-human primates were stimulated with anti-CD3/CD28 antibodies, and inhibitory and apoptotic effects of rapamycin and bortezomib on memory T-cell proliferation were investigated. The CD95 marker in CD3 T cells was used for the separate enrichment of memory T cells and naïve T cells. RESULTS: Rapamycin at the level even higher than therapeutic concentration could not suppress the proliferation of a significant proportion of memory T cells. However, the combined administration of bortezomib and rapamycin abrogated the proliferation of rapamycin-resistant memory T cells. Furthermore, bortezomib preserved the survival of preexisting CD4FoxP3 regulatory T cells, while inducing apoptosis of CD4FoxP3 conventional T cells. The combined administration of low doses of rapamycin and bortezomib also exerted an additive effect on suppressing T-cell proliferation. Cytokine analysis demonstrated that bortezomib could not only suppress rapamycin-permissive interleukin (IL)-6 production, but also production of interferon (IFN)-γ, IL-4, and IL-10. CONCLUSIONS: This article provides in vitro data from which immunosuppressive regimens for the effective control of memory T cells in non-human preclinical experiments and in clinical trials are selected.