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

J. Hester, A. Schiopu, S. N. Nadig, K. J. Wood*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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 languageEnglish (US)
Pages (from-to)2008-2016
Number of pages9
JournalAmerican Journal of Transplantation
Volume12
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

Keywords

  • Cell therapy
  • T
  • humanized mouse model
  • rejection
  • tolerance

ASJC Scopus subject areas

  • Transplantation
  • Pharmacology (medical)
  • Immunology and Allergy

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