Primary immunodeficiencies in the Netherlands: national patient data demonstrate the increased risk of malignancy.

PURPOSE: To analyze the data of the national registry of all Dutch primary immune deficiency (PID) patients, according to the European Society for Immunodeficiencies (ESID) definitions. RESULTS: In the Netherlands, 745 patients had been registered between 2009 and 2012. An overall prevalence of 4.0 per 100,000 inhabitants was calculated. The most prevalent PID was 'predominantly antibody disorder (PAD)' (60.4%). In total, 118 transplantations were reported, mostly hematopoietic stem cell transplantations (HSCT). Almost 10% of the PID patients suffered from a malignancy, in particular 'lymphoma' and 'skin cancer'. Compared to the general Dutch population, the relative risk of developing any malignancy was 2.3-fold increased, with a >10-fold increase for some solid tumors (thymus, endocrine organs) and hematological disease (lymphoma, leukemia), varying per disease category. CONCLUSIONS: The incidence rate and characteristics of PID in the Netherlands are similar to those in other European countries. Compared to the general population, PID patients carry an increased risk to develop a malignancy.

Efficacy and safety of a nanofiltered liquid intravenous immunoglobulin product in patients with primary immunodeficiency and idiopathic thrombocytopenic purpura.

BACKGROUND AND OBJECTIVES: In the production process of a new 5% liquid intravenous immunoglobulin (IVIG-L) product (Nanogam(®) ), a combined pepsin/pH 4·4 treatment/15-nm filtration (pH 4·4/15NF) step and a solvent-detergent (SD) treatment step were incorporated to improve the virus inactivating/reducing capacity of the manufacturing process. Two prospective uncontrolled multicentre studies were performed to evaluate the safety and efficacy of this product. MATERIALS AND METHODS: Efficacy, including pharmacokinetics, of IVIG-L was studied for 6 months in 18 primary immunodeficiency (PID) patients, succeeded by a long-term follow-up study (mean 2·2 years, n=17). Second, in 24 patients with idiopathic thrombocytopenic purpura (ITP), IVIG-L was studied for efficacy for 14 days. In both studies, adverse events and vital signs were recorded to study safety. RESULTS: In PID patients treated with IVIG-L, 0·60 and 0·38 severe infections per patient per year were reported during, respectively, the short-term and long-term follow-up. Pharmacokinetic studies resulted in an IgG half-life of 30·9 ± 11·3 days and a mean IgG trough level of 6·8 ± 1·2 g/l. In the ITP study, all patients showed an increase in platelet counts after infusion with IVIG-L, and 20/24 patients responded with a platelet count >50 × 10(9) /l (83·3%) within 1 week. IVIG-L infusions did not cause clinical relevant changes in laboratory parameters or vital signs. CONCLUSIONS: In clinical studies, IVIG-L (Nanogam®) demonstrated to be efficacious, well tolerated and safe.

T-cell-pre-stimulated monocytes promote neovascularisation in a murine hind limb ischaemia model.

AIM: Monocytes play a significant role in neovascularisation. The stimuli that differentiate monocytes along a pro-angio-/arteriogenic-supporting pathway are currently unclear. We investigated whether pre-stimulation of human monocytes with soluble T-cell-derived factors improves revascularisation in murine hind limb ischaemia as a new option for therapeutic angio- and arteriogenesis. DESIGN: Human monocytes were cultured with or without soluble T-cell-derived factors. Unstimulated and pre-stimulated monocytes were transfused after induction of hind limb ischaemia in nude mice. METHODS: Blood flow was measured with laser Doppler perfusion imaging. Collaterals were visualised by immunohistochemistry and angiography. Monocytes were characterised by flowcytometry and Bio-Plex assays. RESULTS: Transfusion of T-cell-pre-stimulated monocytes significantly improved blood flow recovery after hind limb ischaemia and increased collateral size and collateral and capillary number in the post-ischaemic paw. Pre-stimulated monocytes produced a wide variety of factors that support neovascularisation such as platelet-derived growth factor-BB, vascular-endothelial growth factor, interleukin-4 and tumour necrosis factor-α. Few transfused human cells were detected in the muscle tissue, suggesting that paracrine rather than direct effects appear responsible for the enhanced recovery of blood flow observed. CONCLUSION: These results show a beneficial role for T-cell-pre-stimulated monocytes in neovascularisation, rendering the monocyte a potential candidate for regenerative cell therapy that promotes revascularisation in peripheral arterial disease patients.

Blood outgrowth endothelial cells from cord blood and peripheral blood: angiogenesis-related characteristics in vitro.

BACKGROUND: Blood outgrowth endothelial cells (BOEC) are good candidates for vascular (re-) generating cell therapy. Although cord blood (CB) BOEC have been reported as more proliferative than peripheral blood (PB) BOEC, not much is known about their functional properties. OBJECTIVES: We have studied the following determinants in BOEC expanded from CB and PB: endothelial phenotype, in vitro adhesion, migration, proliferation, and angiogenic tube forming capacity. METHODS/RESULTS: Endothelial phenotype of BOEC was evaluated by fluorescence activated cell sorting (FACS) analysis and confirmed the presence of endothelial markers including CD31, CD105, CD144, CD146, KDR/VEGFR-2, Tie-2, and TNF-alpha-induced VCAM-1 and ICAM-1. Evaluation of cell proliferation revealed a higher basal proliferation of CB-BOEC, which increased after exposure to bFGF but not VEGF. The lower basal proliferation of PB-BOEC increased with VEGF or bFGF addition. Array analysis of angiogenic genes showed many comparable expressions in both BOEC, and a slightly more pronounced pro-angiogenic profile in CB-BOEC than PB-BOEC. Both BOEC were able to form tubular structures in a three-dimensional fibrin matrix. Tube formation in CB-BOEC was markedly induced by TNF-alpha only and inhibited by anti-urokinase antibodies. It was comparable to that induced by combined addition of TNF-alpha and VEGF or bFGF, while maximal tube formation in PB-BOEC required simultaneous exposure to TNF-alpha/VEGF or TNF-alpha/bFGF. CONCLUSIONS: The endothelial phenotype and characteristics for homing, adhesion, migration, inflammation, and angiogenic tube formation are almost equal for BOEC from CB and PB. A slightly more angiogenic phenotype favors CB-BOEC. However, addition of VEGF to PB-BOEC induces equal proliferation and tube formation.