Preferential induction of Th1 responses by functionally mature hepatic (CD8α- and CD8α+) dendritic cells -: Association with conversion from liver transplant tolerance to acute rejection

被引:54
作者
Morelli, AE
O'Connell, PJ
Khanna, A
Logar, AJ
Lu, L
Thomson, AW
机构
[1] Univ Pittsburgh, Med Ctr, Dept Surg, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA
[3] Univ Pittsburgh, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA
关键词
D O I
10.1097/00007890-200006270-00027
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. Liver grafts are accepted across major histocompatibility barriers in mice without immunosuppressive therapy. Potentially tolerogenic immature donor dendritic cells (DC) may play a key role in this phenomenon, but recovery of purified DC from normal livers for functional analysis is inherently difficult, Administration of in vitro propagated immature donor DC to recipients of different types of allograft can prolong transplant survival. By contrast, marked increases in donor liver DC as the result of Flt3 ligand (FL) administration and the resulting augmentation of allostimulatory activity within host lymphoid tissue, is associated with acute graft rejection. Here, we compared the capacity of in vitro generated normal liver immature DC and FL-treated donor liver DC to induce alloimmune CD4(+) T helper (Th) 1/Th2 and CD8(+) T cytotoxic (Tc) 1/Tc2 responses, in vitro and in vivo. Methods. B10 (H2(b), IA(b)) immature liver DC were propagated from normal hepatic nonparenchymal cells in granulocyte macrophage-colony stimulating factor (GM-CSF) for 6-8 days. Freshly isolated DC from livers of FL-treated mice (FL-liver DC) were cultured overnight (o/n) in GM-CSF, and both myeloid (CD11c(+) CD8 alpha(-)) and lymphoid DC (CD11c(+) CD8 alpha(+)) flow-sorted for functional analysis, Proliferative activity and production of interferon (IFN)-gamma, interleukin (IL)-4, and IL-10 by naive C3H (H2(k), IEk) T cells in response to DC stimulation was assessed by [H-3]thymidine incorporation, and by multicolor flow cytometric analysis, respectively, after 3-day mixed leukocyte reactions. To investigate their in vivo trafficking, B10 DC were injected subcutaneously into normal C3H mice. Sections of lymphoid tissue were immunostained for donor NMC class II+ (IA(b+)) cells, and for IFN-gamma, IL-4, and IL-10 production. Donor cells and clusters of specific cytokine-secreting cells were enumerated. Results. Both in vitro propagated normal liver-derived DC, and freshly isolated bulk FL-liver DC showed an immature phenotype (MHC class IIlo, CD40(-), CD80(-), and CD86(-)) and were weak stimulators of naive allogeneic T cells, After o/n incubation in GMCSF, both CD8 alpha(-) and CD8 alpha(+) FL-liver DC exhibited marked up-regulation of surface MHC class II and costimulatory molecules, and acquired potent stimulatory activity for Th1 (mainly) and Th2 cells. Both in vitro propagated immature DC and o/n-cultured mature FL-liver DC homed in vivo to host lymphoid tissues, but with different kinetics. Whereas the mature allogeneic FL-liver DC induced IFN-gamma(+) clusters in splenic T-cell areas within 2 days, the IFN-gamma response to immature DC was much slower and weaker. Conclusions. FL-treated donor livers that are rejected acutely contain markedly enhanced numbers of myeloid (CD8 alpha(-)) and lymphoid (CD8 alpha(+)) DC, many of which are capable of maturing rapidly into strong inducers of Th1 and Tc1 responses. Substantial differences in quantity, and both the phenotypic and functional characteristics of the DC constituency of donor livers, may contribute significantly toward the distinct outcomes of liver transplant tolerance and rejection.
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收藏
页码:2647 / 2657
页数:11
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