S. Gregori et al., Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D-3 and mycophenolate mofetil treatment mediate transplantation tolerance, J IMMUNOL, 167(4), 2001, pp. 1945-1953
1 alpha ,25-Dihydroxyvitamin D-3, the active form of vitamin D3, and mycoph
enolate mofetil, a selective inhibitor of T and B cell proliferation, modul
ate APC function and induce dendritic cells (DCs) with a tolerogenic phenot
ype. Here we show that a short treatment with these agents induces toleranc
e to fully mismatched mouse islet allografts that is stable to challenge wi
th donor-type spleen cells and allows acceptance of donor-type vascularized
heart grafts. Peritransplant macrophages and DCs from tolerant mice expres
s down-regulated CD40, CD80, and CD86 costimulatory molecules. In addition,
DCs from the graft area of tolerant mice secrete, upon stimulation with CD
4(+) cells, 10-fold lower levels of IL-12 compared with DCs from acutely re
jecting mice, and induce a CD4(+) T cell response characterized by selectiv
e abrogation of IFN-gamma production. CD4(+) but not CD8(+) or class II+ ce
lls from tolerant mice, transferred into naive syngeneic recipients, preven
t rejection of donor-type islet grafts. Graft acceptance is associated with
impaired development of IFN-gamma -producing type 1 CD4(+) and CD8(+) cell
s 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 s
yngeneic recipients from islet allograft rejection. These results demonstra
te that a short treatment with immunosuppressive agents, such as 1 alpha ,2
5-dihydroxyvitamin D-3/mycophenolate mofetil, induces tolerance to islet al
lografts associated with an increased frequency of CD4(+)CD25(+) regulatory
cells that can adoptively transfer transplantation tolerance.