To achieve the goal of sustained donor-specifi c transplantation (Tx) tolerance,
research efforts are now focusing on therapies based on specifi c cell subsets with
regulatory properties. We and others have previously highlighted the therapeutic
potential of naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTreg) in
promoting long-term graft acceptance. Using more stringent experimental Tx models,
we were however confronted to limitations. Indeed, while the transfer of antigenspecifi
c nTreg promoted long-term MHC-mismatched skin allograft acceptance in
lymphopenic mice in the absence of any immunosuppressive drug, allograft survival
was only slightly prolonged when nTreg were transferred alone into non-lymphopenic
mice. This suggested that in more stringent conditions, adjuvant therapies may be
needed to effectively control alloreactive T cells (Teff).
Whether and how the expansion of the Treg pool could be best combined with
current immunosuppressive regimens in clinical settings remains to be defi ned. In
this study, we have used in vitro assays and an in vivo skin Tx model to investigate
the effects of various immunosuppressive drugs on the survival, proliferation and
effector function of Teff and nTreg in response to alloantigens. Teff proliferation
was inhibited in a dose-dependent manner by rapamycin and cyclosporine A, while
anti-CD154 mAb only marginally affected Teff survival, proliferation and effector
fucntion in vitro. Rapamycin promoted apoptosis of Teff as compared to nTreg that
were more resistant in the presence of IL-2. In vivo, the transfer and/or expansion
of Treg could be advantageously combined with rapamycin and anti-CD154 mAb
treatment to signifi cantly prolong MHC-mismatched skin allografts survival in
non-lymphopenic recipients.
Taken together our data indicate that immunosuppressive drugs differentially
target T-cell subsets and that some regimens could promote Treg expansion while
controlling the Teff pool in response to alloantigens.