Dextran Sulfate Protects Pancreatic ß-Cells, Reduces Autoimmunity, and Ameliorates Type 1 Diabetes.

A failure in self-tolerance leads to autoimmune destruction of pancreatic ß-cells and type 1 diabetes (T1D). Low-molecular-weight dextran sulfate (DS) is a sulfated semisynthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic ß-cells, reduce autoimmunity, and ameliorate T1D is unknown. In this study, we report that DS, but not dextran, protects human ß-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a proinflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in prediabetic NOD mice and, most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases ß-cell death, enhances islet heparan sulfate (HS)/HS proteoglycan expression, and preserves ß-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory costimulatory molecule programmed death-1 (PD-1) in T cells, reduces interferon-γ+CD4+ and CD8+ T cells, and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on ß-cell protection, extracellular matrix preservation, and immunomodulation can reverse diabetes in NOD mice, highlighting its therapeutic potential for the treatment of T1D.

PLG scaffold delivered antigen-specific regulatory T cells induce systemic tolerance in autoimmune diabetes.

Islet transplantation is a promising treatment for human type 1 diabetes mellitus. Transplantation requires systemic immunosuppression, which has numerous deleterious side effects. Islet antigen-specific regulatory T cells (Tregs) have been shown to protect islet grafts from autoimmune destruction in the nonobese diabetic (NOD) model when co-localized in the kidney capsule. An extra-hepatic transplant site was established by transplanting islet-loaded microporous poly (lactide-co-glycolide) (PLG) scaffolds into abdominal fat. This study examined an autoimmune transplantation model and determined whether co-localized Tregs could protect islet grafts in an extra-hepatic and extra-renal transplant site. Normoglycemia was restored, and co-transplanted Tregs extended graft survival, including several instances of indefinite protection. Transplanted Tregs were replaced by recipient-derived Tregs over time, indicating that islet antigen-specific Tregs induce tolerance to islet grafts through host-derived Tregs. Thus, Tregs provided protection against a diverse repertoire of autoreactive T-cell-receptor specificities mediating diabetes in the NOD model, possibly through a phenomenon previously described as infectious tolerance. Interestingly, the infiltration by Tregs protected a second islet transplant, indicating systemic tolerance to islet antigens. In summary, PLG scaffolds can serve as an alternative delivery system for islet transplantation that allows for the co-localization of immunomodulatory cells within islet grafts and induces long-term graft survival in an autoimmune diabetes model. This method of co-localizing immunomodulatory cells with islets in a clinically translatable transplant site to affect the immune system on a local and systemic level has potential therapeutic implications for human islet transplantation.

Cardiovascular considerations of attention deficit hyperactivity disorder medications: a report of the European Network on Hyperactivity Disorders work group, European Attention Deficit Hyperactivity Disorder Guidelines Group on attention deficit hyperactivity disorder drug safety meeting.

Regulatory decisions regarding attention deficit hyperactivity disorder drug licensing and labelling, along with recent statements from professional associations, raise questions of practice regarding the evaluation and treatment of patients with attention deficit hyperactivity disorder. To address these issues for the European community, the European Network for Hyperkinetic Disorders, through its European Attention Deficit Hyperactivity Disorder Guidelines Group, organised a meeting between attention deficit hyperactivity disorder specialists, paediatric cardiovascular specialists, and representatives of the major market authorisation holders for attention deficit hyperactivity disorder medications. This manuscript represents their consensus on cardiovascular aspects of attention deficit hyperactivity disorder medications. Although sudden death has been identified in multiple young individuals on attention deficit hyperactivity disorder medication causing regulatory concern, when analysed for exposure using currently available data, sudden death does not appear to exceed that of the general population. There is no current evidence to suggest an incremental benefit to electrocardiography assessment of the general attention deficit hyperactivity disorder patient. Congenital heart disease patients have an increased prevalence of attention deficit hyperactivity disorder, and can benefit from attention deficit hyperactivity disorder therapies, including medication. The attention deficit hyperactivity disorder specialist is the appropriate individual to evaluate benefit and risk and recommend therapy in all patients, although discussion with a heart specialist is reasonable for congenital heart disease patients. For attention deficit hyperactivity disorder patients with suspected heart disease or risk factor/s for sudden death, assessment by a heart specialist is recommended, as would also be the case for a non-attention deficit hyperactivity disorder patient. The identification of risk factors for sudden death should not automatically exclude the use of attention deficit hyperactivity disorder medication.

Tissue engineering tools for modulation of the immune response.

Tissue engineering scaffolds have emerged as a powerful tool within regenerative medicine. These materials are being designed to create environments that promote regeneration through a combination of: (i) scaffold architecture, (ii) the use of scaffolds as vehicles for transplanting progenitor cells, and/or (iii) localized delivery of inductive factors or genes encoding for these inductive factors. This review describes the techniques associated with each of these components. Additionally, the immune response is increasingly recognized as a factor influencing regeneration. The immune reaction to an implant begins with an acute response to the injury and innate recognition of foreign materials, with the subsequent chronic immune response involving specific recognition of antigens (e.g., transplanted cells) by the adaptive immune response, which can eventually lead to rejection of the implant. Thus, we also describe the impact of each component on the immune response, and strategies (e.g., material design, anti-inflammatory cytokine delivery, and immune cell recruitment/transplantation) to modulate, yet not eliminate, the local immune response in order to promote regeneration, which represents another important tool for regenerative medicine.

The contribution of plasmid design and release to in vivo gene expression following delivery from cationic polymer modified scaffolds.

Tissue engineering scaffolds capable of gene delivery can provide a structure that supports tissue formation while also inducing the expression of inductive factors. Sustained release strategies are hypothesized to maintain elevated plasmid concentrations locally that can enhance gene transfer. In this report, we investigate the relationship between plasmid release kinetics and the extent and duration of transgene expression. Scaffolds were fabricated from polymer microspheres modified with cationic polymers (polyethylenimine, poly(L-lysine), poly(allylamine hydrochloride), polydiallyldimethylammonium) or polydopamine (PD), with PD enhancing incorporation and slowing release. In vivo implantation of scaffolds into the peritoneal fat pad had no significant changes in the level and duration of transgene expression between PD and unmodified scaffolds. Control studies with plasmid dried onto scaffolds, which exhibited a rapid release, and scaffolds with extended leaching to reduce initial quantities released had similar levels and duration of expression. Changing the plasmid design, from a cytomegalovirus (CMV) to an ubiquitin C (UbC) promoter substantially altered the duration of expression. These studies suggest that the initial dose released and vector design affect the extent and duration of transgene expression, which may be sustained over several weeks, potentially leading to numerous applications in cell transplantation and regenerative medicine.