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 Treg 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
Highlights
The mammalian target of rapamycin, a serine/threonine protein kinase, is inhibited by the immunosuppressive drug rapamycin. mTOR plays a key role in the regulation of cell proliferation, adhesion and survival by integrating information from the cell’s environment 1–3)
We have investigated the influence of combined therapy using low-dose rapamycin and subtherapeutic numbers of ex vivo expanded human CD127loCD25+CD4+FOXP3+ Treg on allograft rejection, as demonstrated by transplant arteriosclerosis (TA) development in the humanized mouse model of arterial transplantation
It has previously been shown that rapamycin monotherapy at a daily dose of 500 lg/kg administered for 28 days prevented TA development in a similar mouse model of human arterial transplantation [14]
Summary
The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, is inhibited by the immunosuppressive drug rapamycin. mTOR plays a key role in the regulation of cell proliferation, adhesion and survival by integrating information from the cell’s environment 1–3). By targeting mTOR, rapamycin inhibits the proliferation of many cell types including T cells, one of the key cellular mediators of rejection following transplantation. T cells are a heterogenous population of lymphocytes with different subsets having different functional capabilities. T cells exhibit plasticity enabling some populations to change their functional properties depending on the environmental cues they receive both as they differentiate, as well as when they function in vivo [4]. Each T-cell subset demonstrates a differential sensitivity to mTOR inhibition [5]. The impact of rapamycin therapy in vivo may be different depending on the composition of the T-cell compartment in the host, the microenvironment in which a T cell is functioning, and the duration and dose of rapamycin therapy
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