Submitted May 9, 2006
Accepted July 13, 2006
The immunosuppressive drug FK778 induces regulatory
activity in stimulated human CD4+CD25- T cells
Ellen Kreijveld, Hans J Koenen, Luuk B Hilbrands, Hans J van Hooff, and Irma Joosten*
Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
Radboud University Nijmegen Medical Centre, The Netherlands
Department of Internal Medicine, University Hospital Maastricht, Maastricht, the Netherlands
* Corresponding author; email: i.joosten{at}abti.umcn.nl.
The induction of transplantation tolerance involves a T-
cell mediated process of immune regulation. In clinical
transplantation, the use of immunosuppressive drugs that
promote or facilitate this process would be highly
desirable. Here, we investigated the tolerance-promoting
potential of the immunosuppressive drug FK778, currently
under development for clinical therapy. Using a human
allogeneic in vitro model we showed that, upon TCR
triggering, FK778 induced a regulatory phenotype in
CD4+CD25- T cells. Purified CD4+CD25- T cells primed in
the presence of FK778, showed hyporesponsiveness upon
restimulation with alloantigen in the absence of the
drug. This anergic state was reversible by exogenous IL-
2 and was induced independent of naturally occurring
CD4+CD25+ regulatory T cells. Pyrimidine restriction was
a crucial requirement for the de novo induction of
regulatory activity by FK778. The FK778 induced anergic
cells showed suppressor activity, in a cell-cell contact
dependent manner, were CD25high, CD45RO+, CD27-, CD62L-,
and expressed CTLA-4, GITR and FoxP3. The cells revealed
delayed p27kip1 degradation and enhanced phosphorylation
of STAT3. In conclusion, the new drug FK778 shows
tolerizing potential through the induction of a
regulatory T cell subset in CD4+CD25- T cells.
