Directed differentiation of regulatory T cells from naive T cells and prevention of their inflammation-mediated instability using small molecules.

Regulatory T (Treg ) cell therapy is a promising approach for immune tolerance induction in autoimmunity conditions and cell/organ transplantations. Insufficient isolation yields and impurity during downstream processes and Treg instability after adoptive transfer in inflammatory conditions are major limitations to Treg therapy, and indicate the importance of seeking a valid, reliable method for de-novo generation of Tregs . In this research, we evaluated Treg -like cells obtained from different Treg differentiation protocols in terms of their yield, purity and activity. Differentiation was performed on naive CD4+ cells and a naive CD4+ /Treg co-culture by using three different protocols - ectopic expression of forkhead box protein P3 (E-FoxP3), soluble transforming growth factor ß (S-TGF) and small molecules [N-acetyl puromycin and SR1555 (N-Ac/SR)]. The results showed that a high yield of a homogeneous population of Treg -like cells could be achieved by the N-Ac/SR method under a T helper type 17 (Th17)-polarizing condition, particularly interleukin (IL)-6 and TGF-ß, when compared with the E-FoxP3 and S-TGF methods. Surprisingly, SR completely inhibited the differentiation of IL-17-producing cells and facilitated Treg generation in the inflammatory condition and had highly suppressive activity against T cell proliferation without Treg -specific demethylase region (TSDR) demethylation. For the first time, to our knowledge, we report the generation of efficient, pure Treg -like cells by using small molecules during in-vitro inflammatory conditions. Our results suggested that the N-Ac/SR method has several advantages for Treg generation when compared with the other methods, including a higher purity of Tregs , easier procedure, superior suppressive activity during the inflammatory condition and decreased cost.

Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency

Background: Common variable immunodeficiency (CVID) is one of the most prevalent symptomatic primary immunodeficiencies (PIDs), which manifests a wide clinical variability such as autoimmunity, as well as T cell and B cell abnormalities. Methods: A total of 72 patients with CVID were enrolled in this study. Patients were evaluated for clinical manifestations and classified according to the presence or absence of autoimmune disease. We measured regulatory T cells (Tregs) and B-cell subsets using flow cytometry, as well as specific antibody response (SAR) to pneumococcal vaccine, autoantibodies and anti-IgA in patients. Results: Twenty-nine patients (40.3%) have shown at least one autoimmune manifestation. Autoimmune cytopenias and autoimmune gastrointestinal diseases were the most common. A significant association was detected between autoimmunity and presence of hepatomegaly and splenomegaly. Among CVID patients, 38.5% and 79.3% presented a defect in Tregs and switched memory B-cells, respectively, whereas 69.0% presented CD21low B cell expansion. Among patients with a defect in Treg, switched memory and CD21low B cell, the frequency of autoimmunity was 80.0%, 52.2% and 55.0%, respectively. A negative correlation was observed between the frequency of Tregs and CD21low B cell population. 82.2% of patients had a defective SAR which was associated with the lack of autoantibodies. Conclusions: Autoimmunity may be the first clinical manifestation of CVID, thus routine screening of immunoglobulins is suggested for patients with autoimmunity. Lack of SAR in CVID is associated with the lack of specific autoantibodies in patients with autoimmunity. It is suggested that physicians use alternative diagnostic procedures (AU)

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Systematic investigation for underlying causes of recurrent infections in children: surveillance of primary immunodeficiency.

Summary: Recurrent infections seem to be a common complaint in children who are referred to general practitioners and pediatricians offices. Detection of primary immunodeficiencies (PID) etiology is very important for achieving appropriate diagnosis and treatment of these patients. The absence of appropriate treatment could lead to subsequent complications, in a hospital inpatient and/or outpatient settings. This study was performed in a group of children with recurrent infections to identify patients with underlying PID. A cross-sectional study was designed to evaluate the final clinical diagnosis obtained in 100 pediatric patients with a history of recurrent infections referred to Children s Medical Center, Tehran, Iran, during one year (2011-2012). History taking and physical examination, complementary laboratory tests including immunological investigations were done to confirm the main causes of disease according to our previously published stepwise approach to recurrent infections. Among all studied patients, 21% (11 males and 10 females) were diagnosed to have PID. Parental consanguinity (p = 0.001) and soft tissue infections (p = 0.004) were significantly higher in PID group, comparing to other causes of recurrent infections. Gender and location of infections were also linked to the type of PID including antibody deficiency, combined immunodeficiency and phagocytosis disorders. The real rate of PID as a cause of recurrent infection appears to be much higher than what is generally considered in a se-lected group of pediatric patients; so, following the suggested stepwise guideline can im-prove timely diagnosis and appropriate treatment of these patients.

Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is one of the most prevalent symptomatic primary immunodeficiencies (PIDs), which manifests a wide clinical variability such as autoimmunity, as well as T cell and B cell abnormalities. METHODS: A total of 72 patients with CVID were enrolled in this study. Patients were evaluated for clinical manifestations and classified according to the presence or absence of autoimmune disease. We measured regulatory T cells (Tregs) and B-cell subsets using flow cytometry, as well as specific antibody response (SAR) to pneumococcal vaccine, autoantibodies and anti-IgA in patients. RESULTS: Twenty-nine patients (40.3%) have shown at least one autoimmune manifestation. Autoimmune cytopenias and autoimmune gastrointestinal diseases were the most common. A significant association was detected between autoimmunity and presence of hepatomegaly and splenomegaly. Among CVID patients, 38.5% and 79.3% presented a defect in Tregs and switched memory B-cells, respectively, whereas 69.0% presented CD21low B cell expansion. Among patients with a defect in Treg, switched memory and CD21low B cell, the frequency of autoimmunity was 80.0%, 52.2% and 55.0%, respectively. A negative correlation was observed between the frequency of Tregs and CD21low B cell population. 82.2% of patients had a defective SAR which was associated with the lack of autoantibodies. CONCLUSIONS: Autoimmunity may be the first clinical manifestation of CVID, thus routine screening of immunoglobulins is suggested for patients with autoimmunity. Lack of SAR in CVID is associated with the lack of specific autoantibodies in patients with autoimmunity. It is suggested that physicians use alternative diagnostic procedures.

New therapeutic approach by sirolimus for enteropathy treatment in patients with LRBA deficiency.

SUMMARY: Purpose. To report the successful use of sirolimus for management of enteropathy in four patients with LPS-responsive beige-like anchor protein (LRBA) deficiency. Methods. Case series. Results. sirolimus therapy led to a complete improvement of symptoms including decrease in frequency and severity of diarrhea, as well as patients' weight gain. No signs of abdominal cramps and anorexia were also detected during the follow up period after treatment. Conclusions. sirolimus with its potential efficacy and immunomodulatory properties may be recommended for the treatment of severe enteropathy refractory to conventional therapy in patients with LRBA deficiency.

Natriuretic peptides and their therapeutic potential in heart failure treatment: An updated review.

Brain natriuretic peptide (BNP), also known as a B-type natriuretic peptide, is one of the important biomarkers with a proven role in the diagnosis of congestive heart failure (CHF). Researchers from the different clinical field have researched into the performance features of BNP testing in the acute care set-up to assist and improve in diagnosing CHF and in predicting future morbidity and mortality rates. The potency of BNP has also been researched into in cases like myocardial ischemia and infarction, cor pulmonale, and acute pulmonary embolism (PE). Based on their vaso-dilatory and diuretic properties and ability to inhibit renin-angiotensin-aldosterone system, natriuretic peptides are able to provide an efficient technique and mechanism of action in the pathophysiologic framework for CHF treatment and management. Recent clinical studies reported that ularitide, a synthetic form of urodilatin, secreted by kidney may be effective in managing and treatment of decompensated heart failure. It has also been reported that Nesiritide, a recombinant natriuretic peptide has been proven to improve dyspnea and hemodynamic parameters in heart failure patients. This review provides an update on natriuretic peptides and their therapeutic potential in CHF treatment.

Design and fabrication of a nanofibrous polycaprolactone tubular nerve guide for peripheral nerve tissue engineering using a two-pole electrospinning system.

Nerve guidance conduits are considered to be the new generation of scaffolds designed for nerve disorders. A tubular construct with a highly aligned fibrous structure, mimicking the endoneurium layer surrounding inner axons of a nerve fascicle, is a suitable candidate for a nerve guide. In this paper a new approach for the fabrication of 3D tubular nerve guides is introduced using simulation of a two-pole electrospinning system and describing its mechanism. The structure of this scaffold is then optimized using the Taguchi statistical method and after morphological studies by scanning electron microscopy, the crystallinity, tensile strength and protein adsorption of these highly aligned fibres are investigated, comparing them with semi-aligned and random fibres produced via conventional mandrel electrospinning. Cell attachment, proliferation and migration of PC12 neuronal like cells are studied on highly aligned, semi aligned and random structures, and morphological change and elongation are observed in PC12 cells. The results of these studies suggest that conduits fabricated using two-pole electrospinning are a suitable and promising scaffold for peripheral and even spinal nerve regeneration. This nerve guide has a great potential for further advanced modifications and regeneration in higher levels.

A structural model of the anaphase promoting complex co-activator (Cdh1) and in silico design of inhibitory compounds.

Anaphase promoting complex (APC) controls cell cycle and chromosome segregation. The APC activation occurs after binding of co-activators, cdh1 and cdc20. Cdh1 plays a role in cancer pathogenesis and is known as a potential drug target. The main aim of this study was prediction of 3D structure of cdh1 and designing the inhibitory compounds based on the structural model. First, 3D structure of cdh1 was predicted by means of homology modelling and molecular dynamics tools, MODELLER and Gromacs package, respectively. Then, inhibitory compounds were designed using virtual screening and molecular docking by means AutoDock package. The overall structure of cdh1 is propeller like and each DW40 repeat contains four anti-parallel beta-sheets. Moreover, binding pocket of the inhibitory compounds was determined. The results might be helpful in finding a suitable cdh1 inhibitor for the treatment of cancer.