In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be... Show moreIn kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level. Show less
In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of... Show moreIn kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants. Show less
Background: The massive pulmonary neutrophil influx in respiratory distress syndrome (RDS) in preterm infants has been ascribed to the effect of leukotriene B-4 (LTB4). Objectives: To investigate... Show moreBackground: The massive pulmonary neutrophil influx in respiratory distress syndrome (RDS) in preterm infants has been ascribed to the effect of leukotriene B-4 (LTB4). Objectives: To investigate whether secretory phospholipase A(2) (sPLA(2)), the rate-limiting enzyme in LTB4 production, is present in lungs of RDS infants and stimulates neutrophil migration. Methods: sPLA(2) was measured in tracheal aspirates from 15 preterm infants with RDS. The effect of aspirates on cord blood neutrophil migration was first measured, and the contribution of sPLA(2) was assessed by addition of its endogenous inhibitor Clara cell protein (CC16) or absorption of sPLA(2) from the aspirates. The role of intracellular signal transduction activation and LTB4 formation in sPLA(2)-induced neutrophil migration was determined using purified sPLA(2), several inhibitors of signal transduction, a LTB4 synthesis inhibitor and a LTB4 receptor antagonist. Results: All aspirates contained sPLA(2), which significantly stimulated neutrophil migration. Addition of CC16 or absorption of sPLA(2) abolished the stimulatory effect. All inhibitors significantly reduced sPLA(2)-induced neutrophil migration. Conclusions: sPLA(2) is present in tracheal aspirates of preterm infants with RDS. Human recombinant sPLA(2) and pancreatic type sPLA(2) stimulate in vitro cord blood neutrophil migration via activation of intracellular signal transduction pathways, LTB4 production and receptor binding. We speculate that sPLA(2) contributes to pulmonary neutrophil influx in RDS. Further studies are needed to determine the potential of sPLA(2) inhibition as a treatment for RDS. Copyright (C) 2009 S. Karger AG, Basel Show less
