Low-dose rapamycin treatment increases the ability of human regulatory T cells to inhibit transplant arteriosclerosis in vivo

Regulatory T cells (T_reg) are currently being tested in clinical trials as a potential therapy in cell and solid organ transplantation. The immunosuppressive drug rapamycin has been shown to preferentially promote T _reg expansion. Here, we hypothesized that adjunctive rapamycin therapy might potentiate the ability of ex vivo expanded human T_reg to inhibit vascular allograft rejection in a humanized mouse model of arterial transplantation. We studied the influence of combined treatment with low-dose rapamycin and subtherapeutic T_reg numbers on the development of transplant arteriosclerosis (TA) in human arterial grafts transplanted into immunodeficient BALB/cRag2^-/-Il2rg^-/- mice reconstituted with allogeneic human peripheral blood mononuclear cell. In addition, we assessed the effects of the treatment on the proliferation and apoptosis of naïve/effector T cells. The combined therapy efficiently suppressed T-cell proliferation in vivo and in vitro. Neointima formation in the human arterial allografts was potently inhibited compared with each treatment alone. Interestingly, CD4⁺ but not CD8⁺ T lymphocytes were sensitive to T_reg and rapamycin-induced apoptosis in vitro. Our data support the concept that rapamycin can be used as an adjunctive therapy to improve efficacy of T_reg-based immunosuppressive protocols in clinical practice. By inhibiting TA, T_reg and rapamycin may prevent chronic transplant dysfunction and improve long-term allograft survival. The authors show that adjunctive low-dose rapamycin therapy potentiates the ability of ex vivo expanded human regulatory T cells to inhibit allograft rejection in a humanized mouse model of arterial transplantation, and further demonstrate that this effect is mediated by suppression of T cell proliferation and induction of CD4+ cell apoptosis.