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Low‐Dose Rapamycin Treatment Increases the Ability of Human Regulatory T Cells to Inhibit Transplant Arteriosclerosis In Vivo
Author(s) -
Hester J.,
Schiopu A.,
Nadig S. N.,
Wood K. J.
Publication year - 2012
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2012.04065.x
Subject(s) - medicine , neointima , in vivo , sirolimus , transplantation , ex vivo , pharmacology , peripheral blood mononuclear cell , transplant rejection , t cell , arteriosclerosis , in vitro , cancer research , cd8 , immunology , immune system , biology , restenosis , biochemistry , microbiology and biotechnology , stent
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/c Rag2 −/− 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.