Dendritic cells and the initiation of the immune response to organ transplants (original) (raw)
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Human Immunology, 1994
Dendritic cell (DC) progenitors were propagated in liquid culture from nonparenchymal cells resident in normal mouse (B10.BR; H-2 k , I-E +) liver in response to granulocyte-macrophage colony stimulating factor (GM-CSF). The liver-derived DC progenitors were MHC class H −/dim and did not express counter receptors for CTLA-4, a structural homologue of the T cell activation molecule CD28. Following subcutaneous or intravenous injection, these liver-derived cells migrated to T cell-dependent areas of lymph nodes and spleen of unmodified, allogeneic (B10; H-2 b ; I-E −) recipients, where they were identified 1-5 days, and 1 and 2 months after injection by their strong surface expression of donor MHC class II (I-E k) and their dendritic morphology. Maximal numbers of liver-derived DC in the spleen were recorded 5 days after injection. Both clusters of strongly donor MHC class II + cells-and (more rarely) dividing cells-could also be identified, suggesting cell replication in situ. Using the same techniques employed to generate DC progenitors from normal liver, GM-CSF-stimulated cells were propagated for 10 days from the bone marrow and spleen of nonimmunosuppressed mice sacrificed 14 days after orthotopic liver transplantation (B10;H-2 b → C3H;H-2 k). Immunocytochemical staining for recipient and donor MHC class II phenotype revealed the growth both of host cells with DC characteristics, and of cells expressing donor alloantigens (I-A b. These results are consistent with the growth, in response to GM-CSF, of donor-derived DC from progenitors seeded from the liver allograft to recipient lymphoid tissue. The functional activity of the progenitors of chimeric DC and the possible role of these cells in the establishment and maintenance of donor-specific tolerance following liver transplantation remain to be determined.
Journal of Experimental Medicine, 1995
Allografts of the liver, which has a comparatively heavy leukocyte content compared with other vascularized organs, are accepted permanently across major histocompatibility complex barriers in many murine strain combinations without immunosuppressive therapy. It has been postulated that this inherent tolerogenicity of the liver may be a consequence of the migration and perpetuation within host lymphoid tissues of potentially tolerogenic donor-derived ("chimeric") leukocytes, in particular, the precursors of chimeric dendritic cells (DC). In this study, we have used granulocyte/macrophage colony-stimulating factor to induce the propagation of progenitors that give rise to DC (CD45+, CD11c+, 33D1+, nonlymphoid dendritic cell 145+, major histocompatibility complex class II+, B7-1+) in liquid cultures of murine bone marrow cells. Using this technique, together with immunocytochemical and molecular methods, we show that, in addition to cells expressing female host (C3H) phenoty...
Distinctive role of donor strain immature dendritic cells in the creation of allograft tolerance
International Immunology, 2006
Dendritic cells (DCs) are pivotal antigen-presenting cells and serve a unique role in initiating immunity. To test the hypothesis that pre-immunization of recipient with certain DC subsets of donor origin can influence graft outcome, we have studied the effects of immunization with allogeneic CD4 + CD8 À CD11c + dendritic cell (CD4 + DC) and CD4 À CD8 + CD11c + dendritic cell (CD8 + DC) on the allograft response. Although both immature CD4 + DC and CD8 + DC subsets from DBA/2 were able to prime naive allogeneic C57BL/6 (B6) T cells in mixed lymphocyte reaction (MLR), CD8 + DC exerted more vigorous alloimmune responses than CD4 + DC did. Also, CD4 + DC-driven allogeneic T cell response was attenuated more significantly by anti-CD154 mAb than CD8 + DC-driven response. Consistent with the MLR results, combined pre-treatment with CD4 + DC, but not CD8 + DC, plus anti-CD154 mAb produced donor strain-specific long-term graft survival and induced tolerance while treatment with CD8 + DC plus anti-CD154 mAb created minimal prolongation of allograft survival in a pancreas islet transplant model (DBA/2/B6). The beneficial effects exerted by CD4 + DC and anti-CD154 mAb pre-treatment were correlated with T h 1 to T h 2 immune deviation and with the amplified donor-specific suppressive capacity by recipient CD4 + CD25 + T cells. These findings highlight the capacity of CD4 + DC to modulate alloimmune responses, and suggest therapeutic approaches for the induction of donor-specific tolerance.
British Journal of Haematology, 2003
Dendritic cells (DCs) are essential for initiating T-cell responses against either host-or leukaemia-specific antigens. We analysed phenotype, allostimulatory capacity and chimaerism of monocyte-derived DCs (moDCs) serially in 28 patients receiving allogeneic stem cell grafts after conventional myeloablative (n ¼ 14) or reduced-intensity conditioning (RIC, n ¼ 14). Although the recovery of phenotype and function of moDCs after myeloablative stem cell transplantation (SCT) was prompt, there was a trend to a lower expression of co-stimulatory molecules and major histocompatibility antigen class II antigens on mature moDCs in patients who had received RIC transplants. Similarly, the allostimulatory capacity of mature moDCs after RIC transplants was reduced for up to 6 months. Six out of 14 (43%) RIC transplant patients showed a pattern of mixed chimaerism within the first 3 months after transplant. RIC transplant patients with a mixed donor DC chimaerism had a significantly higher risk of relapse (75% versus 35% for patients with full donor DC chimaerism, P ¼ 0AE03) but a lower incidence of acute graft-versus-host disease (25% versus 56% for patients with full donor DC chimaerism, P ¼ 0AE157). These data, although preliminary, provide evidence that DC function is impaired after RIC transplants and that DC chimaerism may have an impact on graft-versus-host and graft-versus-leukaemia reactions.