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* Institut National de la Santé et de la Recherche Médicale Unité 437 and Institut de Transplantation et de Recherche en Transplantation, Nantes, France; and
Axe Immunologie, Laboratoires Fournier S.C., Daix, France
A 20-day treatment with LF15-0195, a deoxyspergualine analogue,
induced allograft tolerance in a fully MHC-mismatched heart allograft
model in the rat. Long-term allografts displayed minimal cell
infiltration with no signs of chronic rejection. CD4+
spleen T cells from tolerant LF15-0195-treated recipients were able to
suppress in vitro proliferation of allogeneic CD4+ T cells
and to transfer tolerance to second syngeneic recipients, demonstrating
dominant suppression by regulatory cells. A significant increase in the
percentage of CD4+CD25+ T cells was observed in
the thymus and spleen from tolerant LF15-0195-treated recipient. In
vitro direct stimulation with donor APCs demonstrated that
CD4+ regulatory T cells proliferated weakly and expressed
low levels of IFN-
, IL-10, and IL-2.
CD4+CD25+ cell depletion increased IL-2
production by CD4+CD25- thymic cells, but not
splenic cells. Moreover, tolerance was transferable with splenic and
thymic CD4+CD25+ cells, but also in 50% of
cases with splenic CD4+CD25- cells,
demonstrating that CD25 can be a marker for regulatory cells in the
thymus, but not in the periphery. In addition, we presented evidences
that donor APCs were required to induce tolerance and to expand
regulatory CD4+ T cells. This study demonstrates that
LF15-0195 treatment induces donor APCs to expand powerful regulatory
CD4+CD25+/- T cells present in both the
central and peripheral compartments.
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