Abstract
Regulatory T cells (Treg) 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 Treg 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 Treg 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 Treg and rapamycin-induced apoptosis in vitro. Our data support the concept that rapamycin can be used as an adjunctive therapy to improve efficacy of Treg-based immunosuppressive protocols in clinical practice. By inhibiting TA, Treg 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.
Original language | English (US) |
---|---|
Pages (from-to) | 2008-2016 |
Number of pages | 9 |
Journal | American Journal of Transplantation |
Volume | 12 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2012 |
Keywords
- Cell therapy
- T
- humanized mouse model
- rejection
- tolerance
ASJC Scopus subject areas
- Transplantation
- Pharmacology (medical)
- Immunology and Allergy