Low-dose rapamycin treatment increases the ability of human regulatory T cells to inhibit transplant arteriosclerosis in vivo
(2012) In American Journal of Transplantation 12(8). p.16-2008- Abstract
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... (More)
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.
(Less)
- author
- Hester, J ; Schiopu, A LU ; Nadig, S N and Wood, K J
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- keywords
- Animals, Apoptosis, Arteries/transplantation, Arteriosclerosis/etiology, Cell Proliferation, Dose-Response Relationship, Drug, Humans, Mice, Mice, Inbred BALB C, Sirolimus/pharmacology, T-Lymphocytes, Regulatory/drug effects, Transplantation/adverse effects
- in
- American Journal of Transplantation
- volume
- 12
- issue
- 8
- pages
- 16 - 2008
- publisher
- Wiley-Blackwell
- external identifiers
-
- scopus:84864463754
- pmid:22500984
- ISSN
- 1600-6135
- DOI
- 10.1111/j.1600-6143.2012.04065.x
- language
- English
- LU publication?
- no
- additional info
- © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.
- id
- 94af5db7-d0be-4034-8eaa-7b01dc02e012
- date added to LUP
- 2023-03-10 12:07:48
- date last changed
- 2024-02-02 10:16:32
@article{94af5db7-d0be-4034-8eaa-7b01dc02e012,
abstract = {{<p>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.</p>}},
author = {{Hester, J and Schiopu, A and Nadig, S N and Wood, K J}},
issn = {{1600-6135}},
keywords = {{Animals; Apoptosis; Arteries/transplantation; Arteriosclerosis/etiology; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Mice; Mice, Inbred BALB C; Sirolimus/pharmacology; T-Lymphocytes, Regulatory/drug effects; Transplantation/adverse effects}},
language = {{eng}},
number = {{8}},
pages = {{16--2008}},
publisher = {{Wiley-Blackwell}},
series = {{American Journal of Transplantation}},
title = {{Low-dose rapamycin treatment increases the ability of human regulatory T cells to inhibit transplant arteriosclerosis in vivo}},
url = {{http://dx.doi.org/10.1111/j.1600-6143.2012.04065.x}},
doi = {{10.1111/j.1600-6143.2012.04065.x}},
volume = {{12}},
year = {{2012}},
}