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 call 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 oil memory T-cell proliferation were investigated. The CD95 marker in CD3(+) T cells was used for the separate enrichment of memory T cells and naive 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 CD4(+)FoxP3(+) regulatory T cells, while inducing apoptosis of CD4(+)FoxP3(-) 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)-gamma, 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.