An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice.

Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (Treg) cells, and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved Treg cell specificity. From a panel of rationally designed murine IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg cell selectivity due to increased dependence on the IL-2 receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg cell enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg cell growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared with Fc-fused wild-type IL-2. Preferential Treg cell enrichment was also observed in the presence of activated pathogenic T cells in the pancreas of nonobese diabetic (NOD) mice, despite a loss of Treg cell selectivity in an IL-2R proximal response. These properties facilitated potent and extended resolution of NOD diabetes with infrequent dosing schedules.

Microemulsion-Based Mucoadhesive Buccal Wafers: Wafer Formation, In Vitro Release, and Ex Vivo Evaluation.

Microemulsion has the potentials to enhance dissolution as well as facilitate absorption and permeation of poorly water-soluble drugs through biological membranes. However, its application to govern a controlled release buccal delivery for local treatment has not been discovered. The aim of this study is to develop microemulsion-based mucoadhesive wafers for buccal delivery based on an incorporation of the microemulsion with mucoadhesive agents and mannitol. Ratio of oil to surfactant to water in the microemulsion significantly impacted quality of the wafers. Furthermore, the combination of carbopol and mannitol played a key role in forming the desired buccal wafers. The addition of an extra 50% of water to the formulation was suitable for wafer formation by freeze-drying, which affected the appearance and distribution of carbopol in the wafers. The amount of carbopol was critical for the enhancement of mucoadhesive properties and the sustained drug release patterns. Release study presented a significant improvement of the drug release profile following sustained release for 6 h. Ex vivo mucoadhesive studies provided decisive evidence to the increased retention time of wafers along with the increased carbopol content. The success of this study indicates an encouraging strategy to formulate a controlled drug delivery system by incorporating microemulsions into mucoadhesive wafers.

Strategies of Engineering Nanoparticles for Treating Neurodegenerative Disorders.

BACKGROUND: Neurodegenerative disorders (NDs) are typically referred to Alzheimer's disease, Parkinson's diseases, amyotrophic lateral sclerosis and prion disease. These are commonly debilitating and, unfortunately, have few therapeutic options. OBJECTIVE: In this review, we describe some emerging advances in nanoengineering strategies for the treatment of NDs. One of the main difficulties in fighting against NDs is to overcome the shielding of blood-brain barrier (BBB), which greatly limits the penetration of various therapeutic drugs, which sometimes leads to severe side effects. Nanotechnology, by engineering materials of a size scale usually within 1-100 nm, fortunately offers an alternative approach for novel, promising and innovative solutions. Nanoparticles are capable of not only penetrating the BBB but also releasing active ingredients at a specific site due to its surface functionalization. Therefore, nanoengineered delivery systems potentially facilitate the targeted delivery of neuronal therapeutic drugs and genes to the central nervous system. Furthermore, recently developed nanomaterials are considered as therapeutic agents themselves since they exhibit important roles in promoting the protection of healthy neurons or the regeneration of neurons to repair damaged tissues. CONCLUSION: There have been a variety of innovative approaches to designing therapeutic nanoparticles for NDs, and each has been associated with certain pros and cons.

Amorphous isradipine nanosuspension by the sonoprecipitation method.

The aims of this study are to increase and explain the mechanism of dissolution enhancement of isradipine using the sonoprecipitation method for stable nanosuspensions. There have been still few of published researches on formulation of isradipine using nanoparticle engineering. Nanosuspension systems were prepared upon various factors including amplitude and the time length of ultrasonication. The dissolution test was performed according to the USP paddle method in intestinal fluid (pH 6.8). The crystalline structure of drug, the molecular interaction, morphology and size of nanosuspension were also investigated to determine the mechanism of dissolution enhancement. The sonoprecipitation method with use of HPMC 6 showed its potential in enhancement of the drug release rate. Stable nanosuspension was significantly depended on amplitude and time of ultrasonication since these factors affected on the size of nanoparticles. The synergistic effects of reduction of drug crystallinity and particle size could increase the dissolution rate of isradipine by providing a stable nanosuspension. This work may contribute to a new strategy for improvement dissolution rate of isradipine.

Serum adipokines as biomarkers of beta-cell function in patients with type 1 diabetes: positive association with leptin and resistin and negative association with adiponectin.

BACKGROUND: We investigated the adipokines adiponectin, leptin and resistin as serum biomarkers of beta-cell function in patients with type 1 diabetes. METHODS: One hundred and eighteen patients with type 1 diabetes (20.3 ± 7.5 years) diagnosed <5 years underwent standardized mixed meal test (MMTT) for 2 h. Systemic concentrations of C-peptide, adiponectin, leptin and resistin obtained during MMTT were measured and compared between patient groups by multiple regression analysis. RESULTS: Patients were divided by their adipokine levels in subgroups above or below the median level ('high versus low'). High adiponectin levels (>10.6 µg/mL) were associated with lower C-peptide compared to the low adiponectin subgroup (p < 0.03). Increased leptin or resistin concentrations associated positively with beta-cell function even after adjustment for metabolic confounders (p < 0.04). The described associations between adipokines and C-peptide concentrations persisted in Spearman correlation tests (p < 0.05). Serum adipokines fell during MMTT (p < 0.05). CONCLUSIONS: Serum adipokine levels differentially correlate with beta-cell function in type 1 diabetes independent of BMI or metabolic control. Serum adipokines should be investigated as biomarkers of beta-cell function in prospective studies and intervention trials in type 1 diabetes.

Cellular interferon-γ and interleukin-13 immune reactivity in type 1, type 2 and latent autoimmune diabetes: action LADA 6.

OBJECTIVE: Type 1 diabetes and latent autoimmune diabetes in adults (LADA) are thought to result from immune-mediated ß-cell destruction. It remains unclear why LADA is clinically less severe compared to type 1 diabetes. This study aimed to compare the pro-inflammatory (interferon-γ, IFN-γ) and anti-inflammatory (interleukin-13, IL-13) T-cell responses in humans with LADA and type 1 diabetes. RESEARCH DESIGN AND METHODS: IFN-γ and IL-13 T-cell responses to a panel of 16 (auto)-antigens were tested using an enzyme linked immune-spot technique and peripheral T-cells from 35 patients with type 1 diabetes, 59 patients with type 2 diabetes, 23 LADA patients, and 42 control subjects. RESULTS: LADA and type 1 diabetes patients did not display any statistically significant differences in the frequency of IFN-γ or IL-13 responses to auto-antigenic stimuli, positive control or mitogen. Overall very low T cell reactivity to autoantigens was detected in all groups. IL-13 responses but not IFN-γ responses to recall antigen tetanus toxoid were higher in healthy control subjects compared to patients with type 1 or type 2 diabetes or LADA (P<0.05). Diabetes, independent of type, was associated with weaker response to recall antigen tetanus toxoid. CONCLUSIONS: LADA patients are indistinguishable from type 1 diabetes patients for cellular IFN-γ and IL-13 responses upon mitogen and recall antigen stimulation. These results extend previous findings showing that systemic cytokine/chemokine and humoral responses in type 1 diabetes and LADA are similar.