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Bortezomib Can Suppress Activation of Rapamycin-Resistant Memory T Cells Without Affecting Regulatory T-Cell Viability in Non-Human Primates

2009; Wolters Kluwer; Volume: 88; Issue: 12 Linguagem: Inglês

10.1097/tp.0b013e3181bd7b3a

1534-6080

Jung-Sik Kim, Jae-Il Lee, Joo Young Shin, Su‐Young Kim, Jun‐Seop Shin, Jong-Hyung Lim, Hyoung‐Soo Cho, Il-Hee Yoon, Ki Hyun Kim, Sang‐Joon Kim, Chung‐Gyu Park,

Immunotherapy and Immune Responses

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.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.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.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.