Parenteral lipids impair pneumococcal elimination by human neutrophils.

BACKGROUND: Lipid-induced modulation of phagocyte function seems to contribute to increased susceptibility to infections in patients on parenteral nutrition, and an increased risk for development of pneumonia has been observed in this group. The role of various structurally different lipid emulsions, however, remains unclear. In this study, we therefore assessed phagocyte function, as the capacity of neutrophils to eliminate Streptococcus pneumoniae (i.e. combined result of phagocytosis and killing), in the presence of these lipids. MATERIALS AND METHODS: Neutrophils from six healthy volunteers were incubated for 1 h in emulsions (5 mmol L(-1)) derived from soybean- (LCT), fish- (VLCT), olive- (LCT-MUFA), mixed soybean/coconut oils (LCT/MCTs) or structured lipids (SL). After opsonization of the pneumococci (strain OREP-4) by human immunoglobulins, bacteria and neutrophils were incubated in the presence of complement. Next, pneumococcal elimination was evaluated and expressed as the percentage of bacteria eliminated relative to the initial bacterial numbers in neutrophil-free samples. RESULTS: Neutrophils that were not exposed to lipids showed a pneumococcal elimination capacity of 75 +/- 3% (mean +/- SD). This significantly decreased after exposure to LCT-MUFA (70 +/- 6%), VLCT (67 +/- 2%), SL (63 +/- 9%), LCT (66 +/- 10%) and LCT/MCT (47 +/- 15%). CONCLUSION: These data demonstrate that parenteral lipids impair the microbial elimination capacity of neutrophils in a structure-dependent manner. In accordance with our previously reported in vitro effect on a range of phagocyte functions, LCT/MCT is by far the most potent in this respect.

Human regulatory T cells control xenogeneic graft-versus-host disease induced by autologous T cells in RAG2-/-gammac-/- immunodeficient mice.

PURPOSE: Effective prevention of graft-versus-host disease (GvHD) is a major challenge to improve the safety of allogeneic stem cell transplantation for leukemia treatment. In murine transplantation models, administration of naturally occurring CD4+CD25+ regulatory T cells (Treg) can prevent GvHD. Toward understanding the role of human Treg in stem cell transplantation, we studied their capacity to modulate T-cell-dependent xenogeneic (x)-GvHD in a new model where x-GvHD is induced in RAG2-/-gammac-/- mice by i.v. administration of human peripheral blood mononuclear cells (PBMC). EXPERIMENTAL DESIGN: Human PBMC, depleted of or supplemented with autologous CD25+ Tregs, were administered in mice at different doses. The development of x-GvHD, in vivo expansion of human T cells, and secretion of human cytokines were monitored at weekly intervals. RESULTS: Depletion of CD25+ cells from human PBMC significantly exacerbated x-GvHD and accelerated its lethality. In contrast, coadministration of Treg-enriched CD25+ cell fractions with autologous PBMC significantly reduced the lethality of x-GvHD. Treg administration significantly inhibited the explosive expansion of effector CD4+ and CD8+ T cells. Interestingly, protection from x-GvHD after Treg administration was associated with a significant increase in plasma levels of interleukin-10 and IFN-gamma, suggesting the de novo development of TR1 cells. CONCLUSIONS: These results show, for the first time, the potent in vivo capacity of naturally occurring human Tregs to control GvHD-inducing autologous T cells, and indicate that this xenogeneic in vivo model may provide a suitable platform to further explore the in vivo mechanisms of T-cell down-regulation by naturally occurring human Tregs.