Antithymocyte globulins suppress dendritic cell function by multiple mechanisms.
BACKGROUND
The polyclonal rabbit antithymocyte and anti-T-cell immunoglobulins (ATGs) Thymoglobulin (TG) and ATG-Fresenius S (ATG-F) have been widely used for the prevention and therapy of allograft rejection and graft versus host disease in transplantation. Although immunosuppressive mechanisms of ATGs on T cells are well studied, less is known about their impact on dendritic cells (DCs).


METHODS
Effects of TG and ATG-F on immune functions and signaling pathways of human monocyte-derived DCs were determined by flow cytometry, enzyme-linked immunosorbent assay, Western blot, apoptosis assays, endocytosis assays, and T cell stimulation assays.


RESULTS
TG and ATG-F bind rapidly and with high affinity to CD11c, CD80, CD86, CD40, CD36, CD38, CD206, and human leukocyte antigen-DR on DCs. TG and, to a lesser extent, ATG-F induce apoptosis in immature and mature DCs. Macropinocytotic and receptor-mediated endocytotic antigen uptake in immature DCs is inhibited by TG and ATG-F due to their binding of the C-type lectins CD206 and CD209. TG and ATG-F induce activation of the mitogen-activated protein kinases ERK1/2 and p38 that contributes to the induction of apoptosis. TG and ATG-F also induce cytoplasmic-nuclear translocation of the NF-kappaB/Rel transcription factors RelB, RelA, p50, and p52. Production of interleukin-12p70 in mature DCs is suppressed by TG and ATG-F. TG and ATG-F reduce the capacity of mature DCs to stimulate allogeneic and autologous T cells.


CONCLUSIONS
ATGs interfere with basic DC functions, suggesting that DCs are relevant targets for the immunosuppressive action of ATGs in transplantation.
Naujokat
Cord
C
Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany. cord.naujokat@med.uni-heidelberg.de
Berges
Carsten
C
Fuchs
Dominik
D
Sadeghi
Mahmoud
M
Opelz
Gerhard
G
Daniel
Volker
V
D000911:Antibodies, Monoclonal / Q000276:immunology; D000961:Antilymphocyte Serum / Q000276:immunology*; D017209:Apoptosis; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D011946:Receptors, Antigen / Q000276:immunology
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D011946:Receptors, Antigen; D018664:Interleukin-12; C512542:thymoglobulin; D020928:Mitogen-Activated Protein Kinases