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,25-Dihydroxyvitamin D3 and Mycophenolate Mofetil Treatment Mediate Transplantation Tolerance1
*
Roche Milano Ricerche, and
Department of Medicine, University Vita-Salute, Milan, Italy
1
,25-Dihydroxyvitamin D3, the active form of vitamin
D3, and mycophenolate mofetil, a selective inhibitor of T
and B cell proliferation, modulate APC function and induce dendritic
cells (DCs) with a tolerogenic phenotype. Here we show that a short
treatment with these agents induces tolerance to fully mismatched mouse
islet allografts that is stable to challenge with donor-type spleen
cells and allows acceptance of donor-type vascularized heart grafts.
Peritransplant macrophages and DCs from tolerant mice express
down-regulated CD40, CD80, and CD86 costimulatory molecules. In
addition, DCs from the graft area of tolerant mice secrete, upon
stimulation with CD4+ cells, 10-fold lower levels of IL-12
compared with DCs from acutely rejecting mice, and induce a
CD4+ T cell response characterized by selective abrogation
of IFN-
production. CD4+ but not CD8+ or
class II+ cells from tolerant mice, transferred into naive
syngeneic recipients, prevent rejection of donor-type islet grafts.
Graft acceptance is associated with impaired development of
IFN--producing type 1 CD4+ and CD8+ cells
and an increased percentage of CD4+CD25+
regulatory cells expressing CD152 in the spleen and in the
transplant-draining lymph node. Transfer of
CD4+CD25+ cells from tolerant but not naive
mice protects 100% of the syngeneic recipients from islet allograft
rejection. These results demonstrate that a short treatment with
immunosuppressive agents, such as 1,25-dihydroxyvitamin
D3/mycophenolate mofetil, induces tolerance to islet
allografts associated with an increased frequency of
CD4+CD25+ regulatory cells that can adoptively
transfer transplantation tolerance.
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