TY - JOUR
T1 - Early acceptance of renal allografts in mice is dependent on Foxp3 + cells
AU - Miyajima, Masahiro
AU - Chase, Catharine M.
AU - Alessandrini, Alessandro
AU - Farkash, Evan A.
AU - Della Pelle, Patricia
AU - Benichou, Gilles
AU - Graham, Jay A.
AU - Madsen, Joren C.
AU - Russell, Paul S.
AU - Colvin, Robert B.
N1 - Funding Information:
Supported by a research award from the International Society for Heart and Lung Transplantation (M.M.) and grants from the NIH ( R01HL071932-05A11 to J.C.M.; R56AI081734 and RO1AI081734 to R.B.C.).
PY - 2011/4
Y1 - 2011/4
N2 - Mouse renal allografts have a remarkable ability to promote acceptance across full major histocompatibility complex incompatibilities in certain strain combinations without immunosuppression. The mechanism is unknown but is believed to involve immunoregulation. This study tests whether Foxp3+ T-regulatory cells are responsible in the early phase of graft acceptance, using B6.Foxp3DTR mice that express diphtheria toxin receptor (DTR) in Foxp3+ cells. The administration of DT to B6.Foxp3DTR recipients with accepted DBA/2 kidneys, 3 weeks to 3 months after transplantation, caused a marked depletion of Foxp3 cells and triggered acute cellular rejection, manifested by a sudden increase in blood urea nitrogen within a week. None of the controls showed an increase in blood urea nitrogen, including DT-treated B6 wild-type recipients of DBA/2 kidneys or B6.Foxp3 DTR recipients of isografts. Accepted DBA/2 allografts showed prominent lymphoid sheaths around arteries containing numerous CD3 +Foxp3+ cells, CD4+ cells, dedritic cells, and B cells, which was independent of CCR4. The lymphoid sheaths disintegrate after Foxp3 depletion, accompanied by widespread CD8 interstitial mononuclear inflammation, tubulitis, and endarteritis. The Foxp3 depletion caused an increased frequency of donor-reactive cells in the spleen by interferon (IFN) γ enzyme-linked immunosorbent spot (ELISPOT) assays and increased expression of the maturation markers, CD86 and IAb, on dendritic cells in the spleen and kidney. We conclude that Foxp3+ cells are needed to maintain acceptance of major histocompatibility complex-incompatible renal allografts in the first 3 months after transplantation and may act by inhibiting DC maturation.
AB - Mouse renal allografts have a remarkable ability to promote acceptance across full major histocompatibility complex incompatibilities in certain strain combinations without immunosuppression. The mechanism is unknown but is believed to involve immunoregulation. This study tests whether Foxp3+ T-regulatory cells are responsible in the early phase of graft acceptance, using B6.Foxp3DTR mice that express diphtheria toxin receptor (DTR) in Foxp3+ cells. The administration of DT to B6.Foxp3DTR recipients with accepted DBA/2 kidneys, 3 weeks to 3 months after transplantation, caused a marked depletion of Foxp3 cells and triggered acute cellular rejection, manifested by a sudden increase in blood urea nitrogen within a week. None of the controls showed an increase in blood urea nitrogen, including DT-treated B6 wild-type recipients of DBA/2 kidneys or B6.Foxp3 DTR recipients of isografts. Accepted DBA/2 allografts showed prominent lymphoid sheaths around arteries containing numerous CD3 +Foxp3+ cells, CD4+ cells, dedritic cells, and B cells, which was independent of CCR4. The lymphoid sheaths disintegrate after Foxp3 depletion, accompanied by widespread CD8 interstitial mononuclear inflammation, tubulitis, and endarteritis. The Foxp3 depletion caused an increased frequency of donor-reactive cells in the spleen by interferon (IFN) γ enzyme-linked immunosorbent spot (ELISPOT) assays and increased expression of the maturation markers, CD86 and IAb, on dendritic cells in the spleen and kidney. We conclude that Foxp3+ cells are needed to maintain acceptance of major histocompatibility complex-incompatible renal allografts in the first 3 months after transplantation and may act by inhibiting DC maturation.
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U2 - 10.1016/j.ajpath.2010.12.024
DO - 10.1016/j.ajpath.2010.12.024
M3 - Article
C2 - 21435448
AN - SCOPUS:79953669845
SN - 0002-9440
VL - 178
SP - 1635
EP - 1645
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -