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 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.
Kim
Jung-Sik
JS
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea.
Lee
Jae-Il
JI
Shin
Jin-Young
JY
Kim
Su-Young
SY
Shin
Jun-Seop
JS
Lim
Jong-Hyung
JH
Cho
Hyoung-Soo
HS
Yoon
Il-Hee
IH
Kim
Ki-Hyun
KH
Kim
Sang-Joon
SJ
Park
Chung-Gyu
CG
D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007156:Immunologic Memory / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008253:Macaca mulatta; D008297:Male; D016035:Pancreas Transplantation; D011480:Protease Inhibitors / Q000627:therapeutic use; D011719:Pyrazines / Q000627:therapeutic use*; D020123:Sirolimus / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology
D001897:Boronic Acids; D007166:Immunosuppressive Agents; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D020123:Sirolimus