Biology subjects

Nagy, N.

Publications and source records attributed to Nagy, N..

21 records · Page 2Linked to original sources

bioRxiv2020

Sustained Release of IL-2 Using an Injectable Hydrogel Prevents Autoimmune Diabetes

Interleukin 2 (IL-2) is a promising therapy for autoimmune type 1 diabetes (T1D), but the short half-life in vivo (less than 6 minutes) limits effective tissue exposure to IL-2. Tissue exposure is required for the tolerogenic effects of IL-2. We have developed an injectable hydrogel that incorporates heparin polymers to enable the sustained release of IL-2. This platform uses clinical grade and commercially available materials, including collagen, hyaluronan, and heparin, to deliver IL-2 by slowly degrading and releasing IL-2 over a two-week period in vivo. We find that heparin potentiates the activity of IL-2 and IL-2-mediated expansion of Foxp3+ regulatory T cell (Treg). Hydrogel-mediated IL-2 release showed a reduction of CD4+ and CD8+ T cells and an increase of FoxP3+ Treg in the lymph nodes of injected mice. Moreover, in the Non-Obese Diabetic (NOD) mouse model of T1D once-weekly administration of IL-2 hydrogels prevented diabetes onset as efficiently as 3x weekly repeated injections of soluble IL-2. Together these data suggest that heparin-containing hydrogels may have benefit in delivering low-dose IL-2 and promoting immune tolerance in autoimmune diabetes.

immunology↗

bioRxiv2019

Inter-Species Differences in the Response of Sinus Node Cellular Pacemaking to Changes of Extracellular Calcium

Changes of serum and extracellular ion concentrations occur regularly in patients with chronic kidney disease (CKD). Recently, hypocalcemia, i.e. a decrease of the extra-cellular calcium concentration [Ca2+]o, has been suggested as potential pathomechanism contributing to the unexplained high rate of sudden cardiac death (SCD) in CKD patients. In particular, there is a hypothesis that hypocalcaemia could slow down natural pacemaking in the human sinus node to fatal degrees. Here, we address the question whether there are inter-species differences in the response of cellular sinus node pacemaking to changes of [Ca2+]o. Towards this end, we employ computational models of mouse, rabbit and human sinus node cells. The Fabbri et al. human model was updated to consider changes of intracellular ion concentrations. We identified crucial inter-species differences in the response of cellular pacemaking in the sinus node to changes of [Ca2+]o with little changes of cycle length in mouse and rabbit models (<83 ms) in contrast to a pronounced bradycardic effect in the human model (up to > 1000 ms). Our results suggest that experiments with human sinus node cells are required to investigate the potential mechanism of hypocalcaemia-induced bradycardic SCD in CKD patients and small animal models are not well suited.

cell biology↗

bioRxiv2019

Loss of Y in leukocytes, dysregulation of autosomal immune genes and disease risks

Mosaic loss of chromosome Y (LOY) in leukocytes has been associated with many diseases, yet it remains unclear whether this form of clonal mosaicism exerts a direct physiological effect. Here we perform single-cell and bulk RNA sequencing in leukocytes, observing considerable variation in the rate of LOY across individuals, cell types and disease state. Cells with LOY demonstrated a profound degree of transcriptional dysregulation impacting [~]500 autosomal genes. These genes are preferentially involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y challenging the view of it as a "genetic wasteland". Furthermore, they support the hypothesis that altered immune function in leukocytes is a mechanism directly linking LOY to disease.

immunology↗