Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases.

Glycolipid ligands for invariant natural killer T cells (iNKT cells) are loaded onto CD1d molecules in the late endosome/lysosome. Accumulation of glycosphingolipids (GSLs) in lysosomal storage diseases could potentially influence endogenous and exogenous lipid loading and/or presentation and, thus, affect iNKT cell selection or function. The percentages and frequency of iNKT cells were reduced in multiple mouse models of lysosomal GSL storage disease, irrespective of the specific genetic defect or lipid species stored. Reduced numbers of iNKT cells resulted in the absence of cytokine production in response to alpha-galactosylceramide (alpha-GalCer) and reduced iNKT cell-mediated lysis of wild-type targets loaded with alpha-GalCer. The reduction in iNKT cells did not result from defective expression of CD1d or a lack of antigen-presenting cells. Although H-2 restricted CD4(+) T cell responses were generally unaffected, processing of a lysosome-dependent analogue of alpha-GalCer was impaired in all the strains of mice tested. These data suggest that GSL storage may result in alterations in thymic selection of iNKT cells caused by impaired presentation of selecting ligands.

Glycosphingolipid storage leads to the enhanced degradation of the B cell receptor in Sandhoff disease mice.

Glycosphingolipid storage diseases are a group of inherited metabolic diseases in which glycosphingolipids accumulate due to their impaired lysosomal breakdown. Splenic B cells isolated from NPC1, Sandhoff, GM1-gangliosidosis and Fabry disease mouse models showed large (20- to 30-fold) increases in disease specific glycosphingolipids and up to a 4-fold increase in cholesterol. The magnitude of glycosphingolipid storage was in the order NPC1 > Sandhoff approximately GM1 gangliosidosis > Fabry. Except for Fabry disease, glycosphingolipid storage led to an increase in the lysosomal compartment and altered glycosphingolipid trafficking. In order to investigate the consequences of storage on B cell function, the levels of surface expression of B cell IgM receptor and its associated components were quantitated in Sandhoff B cells, since they are all raft-associated on activation. Both the B cell receptor, CD21 and CD19 had decreased cell surface expression. In contrast, CD40 and MHC II, surface receptors that do not associate with lipid rafts, were unchanged. Using a pulse chase biotinylation procedure, surface B cell receptors on a Sandhoff lymphoblast cell line were found to have a significantly decreased half-life. Increased co-localization of fluorescently conjugated cholera toxin and lysosomes was also observed in Sandhoff B cells. Glycosphingolipid storage leads to the enhanced formation of lysosomal lipid rafts, altered endocytic trafficking and increased degradation of the B cell receptor.

An analysis of the health service efficiency and patient experience with two different intravenous iron preparations in a UK anaemia clinic.

BACKGROUND: Historically, the Renal Unit at King's College Hospital used intravenous (IV) iron sucrose (IS) to treat iron deficiency anaemia in patients with chronic kidney disease who were not on dialysis (CKD-ND). As part of a service initiative to improve patient experience, new products were considered as alternatives. This study investigated the potential impact on patient experience and service costs by switching from IS to ferric carboxymaltose (FCM). METHODS: A decision analytical model was used to calculate the impact of switching from IS to FCM for a cohort of CKD-ND patients. Service provision data were collected for 365 patients who received 600 mg IS within a 12 month period, creating the IS data set. The service provision data, along with a clinically relevant FCM administration protocol (stipulating total doses of 500 mg FCM), were used to calculate a corresponding theoretical data set for FCM for the same cohort of patients. RESULTS: The FCM protocol saved each patient two hospital visits and 2.66 hours of time (equating to approximately a saving of £36.21 in loss of earnings) and £19 in travel costs. Direct attributable costs for iron administration (which included drug, disposables, nursing staff, and hospital-provided patient transport costs) were £58,646 for IS vs £46,473 for FCM. Direct overhead costs (which included nursing preparation time, administration staff, clinic space, and consultant time costs) were £40,172 for the IS service vs £15,174 for the FCM service. LIMITATIONS: Based on clinical experience with the products, this analysis assumes that 500 mg FCM is therapeutically equivalent to 600 mg IS. Consultant time costs are assumed to be the same between the two treatment groups. IV iron administration protocols and data are specific to King's College Hospital. The design is retrospective and changes to the management of the clinic, including service delivery optimization, may also affect real costs. CONCLUSION: FCM was associated with fewer hospital visits and reduced transport costs for CKD-ND patients receiving IV iron and has the potential to save 19-37% in service costs. Owing to increased administration efficiency, FCM can improve the overall patient experience while reducing the total cost of the King's College Hospital IV iron service for CKD-ND patients, compared with treatment with IS.