Abstracts (complete list) - Wissenschaft Online

Marion Schneider, Xuefang Ren, Ying Wang
NK cell targeting of phagocytic dendritic cells
NK dysfunction appears to be responsible for i)massive hemophagocytosis and ii)
exceedingly high concentrations of interferon-g in a disease called hemophagocytic
lymphohistiocytosis (HLH). Genetic NK deficiency is either due to mutations of the
perforin gene, vesicular trafficking molecules such as Munc13-4 or syntaxin11. In
addition, transient NK dysfunction may occur in infectious diseases such as EBV,
leishmaniosis and also in autoimmune diseases. Using in vitro cultures supplemented
with high dose IL-2 (10 3 IU/ml), NK function can be reconstituted in vitro. In the
current study, hemophagocytes were enriched from patients with HLH and phenotyped
by flow cytometry. Phagocytes were then tested as targets in cellular cytotoxicity
assays using IL-2 activated effectors of these patients.
Results: HLH derived phagocytes exhibited a dendritic cell phenotype expressing low
CD80 and CCR7, but high densities of CD40, CD86, CD11c, CD63, CD64, and HLA-DR.
CD209 was variably positive as well as BDCA4, CD1a, CD178 (FAS-Ligand) as well as
TRAIL (tumor necrosis factor related apoptosis inducing ligand) receptor DR4.
Phagocytes often lacked polarization and ultrastructural studies demonstrated even
distribution of Golgi stacks in the cell. cells were derived from patients with HLH as well
as from healthy donors. NK cytolysis by IL-2 acitvated killer effectors (derived from
patients as well as healthy donors) was positive against 51chromium labeled cultured
phagocytes as well as against K562 target cells and against allogeneic, EBV-transformed
B cells. Lytic function was in a large portion independent of calcium and granule release.
In defined effector target combinations, phagocytes were totally resistant to NK
cytolysis. In the presence of TRAIL blocking antibodies, we found that DR4 positive
phagocytes were killed by IL-2 activated receptors but DR4 negative phagocytes were
not killed. We conclude that TRAIL and Trail Receptor DR4 play an important role in NK
control of hemophagocytic cells overactivated in HLH. This context opens new aspects of
treatment and cure.