Search

Peanut allergy is a potentially severe and lifelong allergy, with few effective treatments or preventive measures.To convene an expert panel of allergists, pediatricians, and advocates to discuss and highlight unmet needs in the prevention and management of peanut allergies.Literature searches of PubMed were performed. The panel evaluated published data on the prevention of peanut allergy, treatment of existing peanut allergy, and management of reactions after unintentional peanut exposures.The following key unmet needs in the prevention and management of peanut allergy were identified: (1) enhancing and optimizing implementation of early peanut introduction as a means of preventing the development of peanut allergy, (2) developing knowledge translation strategies regarding the safety and efficacy data for current and emerging immunotherapies for peanut-allergic children to support their use in clinical practice, and (3) promoting understanding of true exposure risk in allergic individuals and ensuring access to epinephrine for unintentional exposures that provoke severe reactions. Practitioners should help educate caregivers about the actual risks associated with peanut allergy and its prevention and management so that treatment decisions can be evidence based rather than fear based. Support tools are needed to help address caregiver goals, expectations, and psychological barriers, as well as identify facilitators for prevention and treatment strategies.There are significant unmet needs in our understanding of peanut allergy; addressing these needs will help to enhance understanding of how to most effectively prevent and treat peanut allergy, as well as educate the food-allergic and nonallergic community regarding current evidence-based practices.

Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.

Recent studies found that mesenchymal stem cells (MSCs), by virtue of their tissue recovery and immunoregulatory properties, have shown a broad prospect for applications in various autoimmune and degenerative diseases. Although the potential therapeutic use of MSCs is considerable, studies and clinical treatment efficacy are preliminary due to the heterogeneity of MSCs. Herein, based on RNA-sequencing (RNA-seq) and single cell sequence properties, we demonstrated that B7-H1 plays an important role in the immunosuppressive function of human gingiva-derived mesenchymal stem cells (GMSCs) in a collagen-induced arthritis murine model that is dependent on STAT3 signaling. Our data offer convincing evidence that B7-H1 expression by GMSCs helps to identify a new subpopulation of MSCs with a greater immunosuppressive property. The approach provides a unique and additional strategy for stem cells-based therapies of autoimmune and other inflammatory diseases., Graphical Abstract, The clinical treatment efficacy of mesenchymal stem cells (MSCs) is preliminary due to the heterogeneity. Wu et al. showed that B7-H1 expression helps to identify a new subpopulation of MSC with a greater immunosuppressive property. The approach provides a unique and additional strategy for stem cells-based therapies of autoimmune diseases.

Anaphylaxis is a severe and potentially life-threatening allergic reaction. Since its discovery over 100 years ago, research has led to great strides in describing pathophysiologic mechanisms of anaphylaxis; however, there is still imprecision regarding its definition and a lack of reliable, confirmatory testing. In this paper, we review definitions of anaphylaxis, highlighting studies examining the utility of the current clinical consensus definition. In addition, we evaluate current difficulties and limitations for both providers in acute care settings managing episodes and allergists evaluating patients after an episode has resolved. Finally, we provide an algorithm for outpatient evaluation of patients with a history of possible anaphylaxis.

Human gingiva-derived mesenchymal stem cells (GMSCs) have been considered to be a better source of MSCs for cell therapy in some immunological diseases. We describe a protocol for isolation and culture of mesenchymal stem cells (MSCs) from human gingival tissue in detail, which provides a methodology to help clinical researches and clinical trial. GMSCs are generally isolated from a remnant or discarded tissue following a routine dental procedure, then cultured in complete culture medium at 37°C in a humidified tissue culture incubator with 5% CO(2) and 95% O(2). Non-adherent cells are removed after 48~72 h and the fresh medium is replaced. When primary cultures become 80%~90% confluent, the plastic-adherent cells are treated with 0.25% trypsin-EDTA and subcultured. A purified population of GMSCs can be obtained 2-3 weeks after the initiation of culture.

Background Mounting evidence has shown that a novel subset of mesenchymal stem cells (MSCs) derived from human gingiva referred to as gingival mesenchymal stem cells (GMSCs) displays a greater immunotherapeutic potential and regenerative repair expression than MSCs obtained from other tissues. However, the safety of the use of transplanted GMSCs in humans remains unclear. Methods In this study, we evaluated the safety of GMSCs transplanted into mouse, rat, rabbit, beagle dog, and monkey as well as two animal models of autoimmune diseases. Results In short- and long-term toxicity tests, infused GMSCs had no remarkable adverse effects on hematologic and biochemical indexes, particularly on the major organs such as heart, liver, spleen, and kidney in recipient animals. It was also shown that GMSCs were well tolerated in other assays including hemolysis, vascular, and muscular stimulation, as well as systemic anaphylaxis and passive skin Arthus reaction in animal models. GSMC infusion did not cause any notable side effects on animal models of either autoimmune arthritis or lupus. Significantly, GMSCs most likely play no role in genotoxicity and tumorigenesis. The biological features remained stable for an extended period after cell transfer. Conclusions GMSCs are safe in various animal models of autoimmunity, even during active disease episodes, especially in monkeys. This study paves a solid road for future clinical trials of GMSCs in patients with autoimmune and inflammatory diseases. Electronic supplementary material The online version of this article (10.1186/s13287-019-1262-5) contains supplementary material, which is available to authorized users.

BACKGROUND: Bone destruction is one of many severe complications that occurs in patients with rheumatoid arthritis (RA) and current therapies are unable to cure this manifestation. This study here aims to determine whether GMSC can directly inhibit osteoclast formation and eventually attenuate osteoclastogenesis and bone erosion in an inflammatory milieu. METHOD: GMSC were co-cultured with osteoclast precursors with or without CD39 inhibitor, CD73 inhibitor or adenosine receptors inhibitors pretreatment and osteoclast formation were evaluated in vitro. 2×10^6 GMSC per mouse were transferred to CIA mice and pathology scores, the frequency of osteoclasts, bone erosion in joints were assessed in vivo. FINDING: GMSC but not control cells, markedly suppressed human or mice osteoclastogenesis in vitro. GMSC treatment also resulted in a dramatically decreased level of NF-κB p65/p50 in osteoclasts in vitro. Infusion of GMSC to CIA significantly attenuated the severity of arthritis, pathology scores, frequency of osteoclasts, particularly bone erosion, as well as a decreased expression of RANKL in synovial tissues in vivo. Blockade of CD39/CD73 or adenosine receptors has significantly abrogated the suppressive ability of GMSC in vitro and therapeutic effect of GMSC on bone erosion during CIA in vivo. INTERPRETATION: GMSC inhibit osteoclast formation in vitro and in vivo partially via CD39-CD73-adenosine signals. Manipulation of GMSC may have a therapeutic implication on rheumatoid arthritis and other bone erosion related diseases. FUND: This study was supported by grants from the National Key R&D Program of China (2017YFA0105801 to F.H); the Zhujiang Innovative and Entrepreneurial Talent Team Award of Guangdong Province (2016 ZT 06S 252 to F·H) and National Institutes of Health (R01 AR059103, R61 AR073409 and NIH Star Award to S.G.Z).

Background and purpose Regulation of neural inflammation is considered as a vital therapeutic target in ischemic stroke. All-trans retinoic acid (atRA), a potent immune modulator, has raised interest in the field of stroke therapy. However, the immunological mechanisms for atRA-mediated neuroprotection remain elusive. The current study evaluated the impact of atRA on post-stroke neural inflammation and elucidated the mechanisms involved in the regulation of related neutrophil functions. Methods atRA was prophylactically administered to mice 1 day before transient middle cerebral artery occlusion (tMCAO, 1 h) and repeated daily immediately after reperfusion for 3 days. Stroke outcomes, neutrophil polarization, and formation of neutrophil extracellular traps (NETs) in the stroke lesion were assessed. Neutrophil depletion was induced with anti-Ly6G antibodies. Primary neutrophil cultures were used to explore the mechanisms of atRA treatment. Results Prophylactic atRA treatment reduced infarct volumes and neurological deficits at 1 day after tMCAO. Post-stroke neural inflammation was attenuated and neutrophil accumulation in lesion was downregulated. atRA treatment skewed neutrophil toward N2 phenotype which facilitated its clearance by macrophage and inhibited NETs formation. The functions of neutrophil were indispensable in the protective effects of atRA and were associated with suppression to STAT1 signaling by atRA. Administration of atRA after stroke still provided efficient protection to cerebral ischemia. Conclusion atRA displays potent therapeutic efficacy in ischemic stroke by attenuating neural inflammation. Treatment of atRA impeded neutrophil accumulation, favored N2 polarization, and forbade NETs formation in ischemic lesion. STAT1 signaling played a decisive role in the mechanisms of atRA-afforded regulation to neutrophil. Electronic supplementary material The online version of this article (10.1186/s12974-019-1557-6) contains supplementary material, which is available to authorized users.

Introduction Prenatal exposure to di(2-ethylhexyl) phthalate (DEHP) has been reported to be associated with adverse effects on neurodevelopment that yield behavior syndromes in young children with an estimated median exposure lower than the currently recommended tolerable daily intake (TDI) and reference dose (RfD). Objectives Our aim was to derive the benchmark dose for prenatal exposure to DEHP for the neurodevelopmental health in children. Methods A total of 122 mother-child pairs from the Taiwan Maternal and Infant Cohort Study were analyzed for the dose-response relationship between maternal exposure to DEHP and children's behavioral syndromes evaluated at 8 years (n = 122, 2009), 11 years (n = 96, 2012), and 14 years (n = 78, 2015) of age. We employed a multivariate regression model to assess the statistical associations between the estimated maternal average daily intake of DEHP and child's individual CBCL scores for boys and girls at each separate age, followed by a mixed model for all the children across three ages accounting for individual variations. We then employed structural equation models by combining the children's specific behavioral problem scores at different ages and obtained a simulated overall latent score in relation to maternal exposure. Based on the established dose-response relationship, we derived the benchmark dose (BMD) and the lower limit (BMDL). Results Associations of maternal DEHP exposure (median 4.54 μ g / k g _ b w / d a y ) with the Child Behavior Checklist (CBCL) scores were all significant, except for somatic complaints, adjusting for child's age, gender, IQ, and family income. The BMDL, given a benchmark response of 0.10 (0.05) and a background response of 0.05, was 6.01 (2.16) μ g / k g _ b w / d a y for an integrated CBCL score. Conclusions The current TDI (RfD) of 50 (20) μ g / k g _ b w / d a y for DEHP might not protect pregnant women for their children from behavioral problems. There remains the lack of comparable toxicological data. Further investigations are needed.

Tumor Necrosis Factor (TNF) α is a multifunctional cytokine with pro-inflammatory and anti-inflammatory characteristics. Increasing evidence suggests that thymus-derived, natural regulatory T cells (nTreg) express a remarkably high level of TNF Receptor 2 (TNFR2) and TNFα modulates the number or function of nTreg via TNFR2 in autoimmune diseases. Nonetheless, Treg cells consist of at least nTreg and iTreg that are induced in the periphery or in vitro and two subsets may have different biological characteristics. However, the role of TNF-TNFR signaling in development and function of these iTreg cells is less clear. In this study, we systemically studied the effect of TNFα and its receptor signals on iTreg differentiation, proliferation, and function in vitro and in vivo. We further investigated the expression and requirement of TNFR1 or TNFR2 expression on iTreg by utilizing TNFR1−/− and TNFR2−/− mice. We found that exogenous TNFα facilitated iTreg differentiation and function in vitro. TNFR2 deficiency hampered iTreg differentiation, proliferation, and function, while TNFR1 deficiency decreased the differentiation of inflammatory T cells such as Th1 and Th17 cells but maintained the regulatory capabilities of iTreg both in vitro and in vivo. Using colitis model, we also revealed TNFR2 but not TNFR1 deficiency compromised the iTreg functionality. Interestingly, inflammation affects TNFR expression on nTreg but not iTreg subset. Our results demonstrate that exogenous TNFα may enhance the differentiation and function of iTreg via TNFR2 signaling. The expression of TNFR2 on Treg might be downregulated in some autoimmune diseases, accompanied by an increased level of TNFR1. Thus, TNFR2 agonists or TNFR1-specific antagonists hold a potential promise for clinical application in treating patients with autoimmune diseases.

We establish consequences of the moving form of Schmidt's Subspace Theorem. Indeed, we obtain inequalities that bound the logarithmic greatest common divisor of moving multivariable polynomials evaluated at moving $S$-unit arguments. In doing so, we complement recent work of Levin. As an additional application, we obtain results that pertain to the greatest common divisor problem for algebraic linear recurrence sequences. These observations are motivated by previous related works of Corvaja-Zannier, Levin and others., Comment: Final Version. Several Improvements. Published by TAMS

Background The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. Objective ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. Methods Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non–daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. Results Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non–daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non–daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. Conclusions Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.

Space heating and cooling account for major portions of the energy consumption in various types of buildings. Energy use that relies heavily on fossil fuels results in greenhouse gas emissions and ultimately contributes to climate change via global warming. As such, it is important to utilize clean and renewable technologies to meet building energy demands. One such technology is the ground-source heat pump (GSHP), which uses the free and abundant energy from the ground. However, GSHP systems are expensive to install and often suffer from declining efficiencies over time, especially when they are employed in buildings that have unbalanced heating and cooling loads, such as those in extreme Canadian climates. In this study, we introduce a novel concept, a thermal caisson (TC), which not only considerably reduces the capital costs of GSHP systems, but also mitigates their efficiency degradation over time. TCs serve a dual functionality as both structural components that support the building as well as energy system components that provide heating and cooling to buildings. The TC comprises ground heat exchanger loops and a carefully chosen phase change material (PCM), which stores and releases large quantities of latent heat when needed, connected to a high efficiency heat pump inside the building. Results show that TCs could reduce the capital costs of GSHP systems by up to 49% and increase their coefficients of performance by up to 16% (with a median change from 3.7 to 4.3 in January) resulting in much shorter payback periods as well as more stable and improved performance. Compared to fossil-fuel based systems, TCs offer a considerable reduction (close to 30% in this study) in annual operating costs for a much smaller corresponding increase in capital costs. The results suggest that TCs have promise to be widely incorporated in the heating, ventilation, and air-conditioning systems of numerous building types.

K Hasegawa, JM Mansbach, YA Bochkov. JAMA Pediatrics. 2019;61(3):544–552 To evaluate whether bronchiolitis in infancy caused by rhinovirus C is a stronger risk factor for recurrent wheeze than bronchiolitis caused by respiratory syncytial virus (RSV) or rhinovirus A or B. 716 infants in a multi-center prospective cohort study who were hospitalized for bronchiolitis due to rhinovirus and/or RSV from November 2011 – April 2014. The primary exposure of interest was viral infection (RSV, rhinovirus A, B or C) based on PCR of nasopharyngeal samples. The primary outcome was recurrent wheeze by age 3 years (according to 2007 …

To investigate the outcomes of two surgical interventions for Peyronie's disease (PD) with hourglass deformity: partial excision and grafting (PEG) or inflatable penile prosthesis (IPP) implantation.Retrospective data were collected from two centers: Technical University of Munich (PEG) and Tulane University Medical Center (IPP). Collected variables included patient demographics, sexual function, penile vascular measurements, and treatment outcomes.A total of 50 PD patients with hourglass deformity (26 PEG [group 1] and 24 IPP [group 2]) were included in this study. Patients in group 1 had higher mean preoperative Sexual Health Inventory for Men scores (22.2 vs 10.3, P 0001), required less erectile dysfunction treatment (35% vs 79%, P = .005), and had more nonvascular etiology (77% vs 21%, P .0001). There were no intraoperative complications, 2 patients in group 1 had postoperative glans hypoesthesia, and 1 patient in group 2 required surgical revision. All patients in both groups had significant ≥20% improvements in penile curvature with mean changes of 68.1 degrees (12.7) in group 1 and 49.6 degrees (13.5) in group 2, P .0001. Resolution of hourglass deformity was achieved in 85% of patients in group 1 and 100% of patients in group 2, P = .045. The mean postoperative change in Sexual Health Inventory for Men score was -0.3 (1.3) in group 1 and 16.7 (4.7) in group 2, P .0001.Both options provide excellent outcomes for well-selected patients with PD and an hourglass deformity. PEG can be offered to patients with good erectile function, whereas the IPP remains the preferred option for patients with poor erections.

BACKGROUND: Egg allergy is common in young children (

Cell specific and cytokine targeted therapeutics have underperformed in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) have emerged as a novel therapy to address the dysregulation in autoimmune diseases but also have limitations. Human gingiva derived MSCs (GMSCs) are superior in regulating immune responses. Here, we demonstrate that the adoptive transfer of GMSCs homes to and maintains in the kidney and has a robust therapeutic effect in a spontaneous lupus nephritis model. Specifically, GMSCs limits the development of autoantibodies as well as proteinuria, decreases the frequency of plasma cells and lupus nephritis histopathological scores by directly suppressing B cells activation, proliferation and differentiation. The blockage of CD39-CD73 pathway dramatically abrogates the suppressive capacities of GMSCs in vitro and in vivo and highlights the significance of this signaling pathway in SLE. Collectively, manipulation of GMSCs provides a promising strategy for the treatment of patients with SLE and other autoimmune diseases.

Objective To review GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methods and discuss the clinical application of conditional recommendations in clinical guidelines, specifically in the context of anaphylaxis. Data Sources Articles that described GRADE, evidence synthesis, evidence to recommendation frameworks, and shared decision making were used to discuss conditional recommendations of the 2020 Anaphylaxis GRADE guideline. Study Selections A narrative review detailing concepts of GRADE and approaches to translate conditional recommendations to individualized and contextualized patient care. Results GRADE methods encourage a nuanced relationship between certainty of evidence and strength of recommendations. Strength of recommendation must incorporate key factors, including the balance between benefits and harms, patient values and preferences, and resource allocation (costs), with equity, feasibility, and acceptability also often included as considerations. GRADE guidelines provide recommendations that are characterized by directionality (for or against) and strength (strong or conditional). A conditional recommendation is tailored to context and primarily applied through a lens of patient preferences related to the likelihood of outcomes of importance and a shared decision-making approach. Although the 2020 Anaphylaxis GRADE guideline better informs the practice of anaphylaxis prevention through (1) identification and mitigation of risk factors for biphasic anaphylaxis and (2) evaluation of the use of glucocorticoid and/or antihistamine pretreatment, all GRADE recommendations, although directional, are conditional and as such should not be universally applied to every circumstance. Conclusion Clinical guidelines provide an important opportunity to critically appraise evidence and translate evidence to practice. Patients, practitioners, and policy makers should appreciate the strength of recommendation and certainty of evidence and understand how this affects guideline applicability and implementation.

Introduction Les patients traites par AR101, un medicament biologique experimental administre par voie orale dans l’immunotherapie orale a l’arachide, tolerent mieux les proteines d’arachide. La qualite de vie (QdV) a ete evaluee chez des patients de l’etude PALISADE traites 28 ou 56 semaines supplementaires par AR101 (300 mg/jour). Methodes Des patients âges de 8 a 17 ans ont rempli un questionnaire de QdV dans les allergies alimentaires (FAQLQ) adapte a l’âge et un formulaire de mesure independante de l’allergie alimentaire (FAIM) a l’entree et a la sortie de l’etude PALISADE, et a la sortie de l’etude ARC004. Les variations (Δ) du score total et des scores de sous-domaine (selection de PALISADE a sortie d’ARC004, moyenne [IC 95 %]) des cohortes 1 (28 semaines) et 3a (56 semaines) ont ete calculees apres traitement par AR101 300 mg/jour ; une difference minimale importante (DMI) ≥ 0,5 etait consideree cliniquement significative. Resultats Sur 285 patients eligibles traites par AR101 dans PALISADE, respectivement 110 (38,6 %) et 31 (10,9 %) patients ont ete affectes aux cohortes 1 et 3a. Les patients ont rempli le FAQLQ (1 : n = 68 ; 3a : n = 16) et le FAIM (n = 72 ; n = 17). Dans les deux cohortes, la DMI depassait −0,5 pour les scores totaux du FAQLQ (1 : n = 68, Δ = −0,71 [−1,01, −0,41] ; 3a : n = 16, Δ = −0,63 [−1,36, 0,11]) ; les scores de tous les sous-domaines depassaient la DMI dans la cohorte 1 et seul le score Impact emotionnel etait superieur a la DMI dans la cohorte 3a. Les scores totaux du FAIM depassaient aussi la DMI dans les deux cohortes (1 : n = 72, Δ = −0,60 [−0,83, −0,36] ; 3a : n = 17, Δ = −0,83 [−1,39, −0,37]) ; le score Attente de resultats depassait la DMI dans la cohorte 1 et les scores de tous les sous-domaines etaient superieurs a la DMI dans la cohorte 3a. Discussion Les mesures de QdV auto-evaluee depassaient toujours la DMI apres passage a l’etude ARC004 en ouvert a 28 et 56 semaines de traitement supplementaire par AR101. Conclusion Ces donnees suggerent que la QdV specifique a la maladie auto-evaluee s’ameliore apres traitement par AR101 300 mg/jour pendant 28 ou 56 semaines.

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to

Rheumatoid arthritis (RA) is a systemic-autoimmune-mediated disease characterized by synovial hyperplasia and progressive destruction of joint. The aim of this study is to evaluate whether human gingiva derived MSCs (GMSCs) can alleviate rheumatoid arthritis through directly targeting of rheumatoid arthritis synovial fibroblasts (RA-SF) and underlying mechanism(s). GMSCs or Primary Dermal Fibroblast (PDF) were co-cultured with LPS-stimulated RA-SF. The proliferation, migration and invasion abilities of RA-SF or GMSCs treated RA-SF were examined for determining the suppressive effects of GMSCs on RA-SF. To learn whether GMSCs suppress RA-SF migration and invasion in vivo, GMSCs were subcutaneously co-transplanted with RA-SF and health cartilage into SCID mice to develop a humanized synovitis model, H&E or immunofluorescence staining were employed to determine the effects. Moreover, GMSCs were transferred into collagen induced arthritis model (CIA), proliferation, migration and invasion capacities of synovial fibroblasts from model mice or GMSCs treated mice were compared. We found that the proliferation, migration and invasion capacities of GMSCs treated RA SF were significantly declined. Importantly, the expression of IL-6, IL-8, MMP1, MMP2, MMP3 and MMP13 were dramatically reduced in GMSCs treated RA-SF (qPCR results). Administration of GMSCs was therapeutic in collagen induced arthritis synovial fibroblasts pathology (proliferation, migration and invasion). Furthermore, GMSCs directly suppress RA-SF invasion in a humanized synovitis model. We conclude that the manipulation of GMSCs can ameliorate rheumatoid arthritis (RA) through directly targeting of rheumatoid arthritis synovial fibroblasts.

Treg cells play an important role in maintaining immunologic homeostasis. Abnormal Treg were found in some autoimmune diseases. Infusion of natural Treg (nTreg) prevents some autoimmune disease but usually fails to treat established diseases. Several studies demonstrated nTreg could be transdifferentiated into Th17 cells and lost its function under inflammatory condition. Given IL-6 is an important inflammatory cytokine and it binds to its receptor (CD126) to exert functional role, whereas nTreg express CD126, we hypothesize that CD126− Foxp3+ cell subsets could be more stable and functional in the inflammatory condition. CD126+ and CD126− nTreg were sorted from collagen-induced arthritis (CIA) and then were analyzed for transcript difference via RNA-sequence. They were cultured in the presence of IL-6 to determine the stability and function following a colitis model in vivo. Compared to normal mice, the proportion of CD126+ nTreg in CIA was significantly higher. CD126− nTreg express higher immunosuppressive molecules and present stronger function than CD126+ nTreg in both normal condition and presence of IL-6. Moreover, CD126− nTreg was stable while CD126+ nTreg lost Foxp3 expression and trans-differentiated into Th17 in the presence of IL-6. In addition, CD126− nTreg exhibited reduced Hif-1a and glucose transporter 1(Slc2a1) expression, which are two key regulators of glycolytic metabolism and play an important role in the balance of Th17 and Treg. Finally, CD126− Treg more potent treat colitis compared to control. We show CD126− nTreg present stronger function and stability under inflammatory conditions Our results suggest that manipulation of CD126− nTreg might be a novel strategy for the treatment of autoimmune diseases.

Cell specific and cytokine targeted therapeutics have underperformed in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) have emerged as a novel therapy to address the dysregulation in autoimmune diseases but also have limitations. Human gingiva derived MSCs (GMSCs) are superior in regulating immune responses. Here, we demonstrate that the adoptively transferred GMSC home to and maintain in the kidney and have a robust therapeutic effect in a spontaneous lupus nephritis model. Specifically, GMSCs limits the development of autoantibodies as well as proteinuria, decreases the frequency of plasma cells and lupus nephritis histopathological scores by directly suppressing B cells activation, proliferation and differentiation. The blockage of CD39-CD73 pathway dramatically abrogated the suppressive capacities of GMSCs in vitro and in vivo and highlights the significance of this signaling pathway in SLE. Collectively, manipulation of GMSCs provides a promising strategy for the treatment of patients with SLE and other autoimmune diseases.

Apremilast is a novel phosphodiesterase 4 (PDE4) inhibitor suppressing immune and inflammatory responses. We assessed the anti-inflammatory effects of Apremilast in type II collagen (CII) induced arthritis (CIA) mouse model. To determine whether Apremilast can ameliorate arthritis onset in this model, Apremilast was given orally at day 14 after CII immunization. Bone erosion was measured by histological and micro-computed tomographic analysis. Anti-mouse CII antibody levels were measured by enzyme-linked immunosorbent assay, and Th17, Th1 cells, and CD4+Foxp3+ regulatory T (Treg) cells were assessed by flow cytometry in the lymph nodes. Human cartilage and rheumatoid arthritis (RA) synovial fibroblasts (RASFs) implantation in the severe combined immunodeficiency (SCID) mouse model of RA were used to study the role of Apremilast in the suppression of RASFs-mediated cartilage destruction in vivo. Compared to untreated and vehicle control groups, we found that Apremilast therapy delayed arthritis onset and reduced arthritis scores in the CIA model. Total serum IgG, IgG1, IgG2a, and IgG2b were all decreased in the Apremilast treatment groups. Moreover, Apremilast markedly prevented the development of bone erosions in CIA mice by CT analysis. Furthermore, in the Apremilast treated group, the frequency of Th17 cells and Th1 cells was significantly decreased while Treg cells frequency was significantly increased. The high dose of Apremilast (25mg/kg) was superior to low dose (5mg/kg) in treating CIA. Apremilast treatment reduced the migratory ability of RASFs and their destructive effect on cartilage. Compared to the model group, Apremilast treatment significantly reduced the RASFs invasion cartilage scores in both primary implant and contralateral implant models. Our data suggest that Apremilast is effective in treating autoimmune arthritis and preventing the bone erosion in the CIA model, implicating its therapeutic potential in patients with RA.

Background Food allergy affects up to 8% of children in the U.S. There is minimal research to date on food allergy policies that are currently in place in schools and the opinions of parents of children with food allergy on the effectiveness of or need for these policies. Methods An electronic survey was disseminated to parents of children with food allergy. Frequencies were calculated to describe respondent characteristics and responses. Chi-square tests were performed to examine associations between school and child characteristics and outcomes. Results Of the 289 parent respondents, 27.4% were unsure or felt school was unsafe for their child with food allergy. While the majority felt that the polices in their child’s school were helpful, most also believed that implementation of additional polices was necessary, including availability of stock epinephrine (94.2%), lunch menus with allergen information (86%), ingredient labels on food items (81%), and direct food allergy education for students (86%). There were significant differences in school food allergy policy depending on the age of the student body, private versus public school, and geographic location. Conclusions While most schools reportedly have one or more food allergy policies in place, many parents have concerns over the safety of their child at school and feel that additional policies are necessary to improve the safety of the school environment for children with food allergy. The availability of stock epinephrine, improved allergen labeling of food and menus and increased food allergy education may be key policy areas on which to focus.

PURPOSE: Evidence on the long-term impact of testicular cancer treatment on sexual function is not clear. Our aim was to estimate the effect of testicular cancer treatment on the risk of sexual dysfunction in long-term survivors of testicular cancer.MATERIALS AND METHODS: We performed a cross-sectional study of 2,260 long-term survivors of testicular cancer with a median followup of 17 years (IQR 12-24), including 1,098 who underwent orchiectomy alone (surveillance), 788 treated with bleomycin, etoposide and cisplatin alone or post-chemotherapy retroperitoneal surgery, 300 treated with abdominal radiotherapy and 74 who received more than 1 line of treatment. Sexual function was evaluated by the IIEF-15 (International Index of Erectile Function-15) questionnaire. Results were compared between treatment groups using logistic regression analysis with the results on each of the 5 IIEF-15 dimensions as the outcome and treatment as exposure using surveillance as the referent.RESULTS: The risk of erectile dysfunction was increased in all treatment groups compared to surveillance, including bleomycin, etoposide and cisplatin alone (OR 1.5, 95% CI 1.0-2.1, p CONCLUSIONS: Treatment with bleomycin, etoposide and cisplatin, radiotherapy and more than 1 treatment line increased the risk of erectile dysfunction in long-term survivors of testicular cancer compared to surveillance. Patients should be informed about this as part of the information on treatment related late effects.

Rapidly accumulating evidence has now suggested that the long non-coding RNAs (LncRNAs), a large and diverse class of non-coding transcribed RNA molecules with diverse functional roles and mechanisms, play a major role in the pathogenesis of many human inflammatory diseases. Although some LncRNAs are overexpressed in plasma, T cell, and synovial tissues of patients with rheumatoid arthritis (RA), there is a dearth of knowledge in what role these transcripts play in fibroblast-like synoviocytes (FLSs) of these patients. Here, our studies showed that GAPLINC, a newly identified functional LncRNA in oncology, displayed a greater degree of expression in FLSs from RA than in patients with traumatic injury. GAPLINC suppression in RA-FLS cells revealed significant alterations in cell proliferation, invasion, migration, and proinflammatory cytokines production. Additionally, we performed a preliminary bioinformatics analysis of GAPLINC gene sequence in order to find its target molecules, using miRanda, PITA, RNAhybrid algorithms, Kyoto encyclopedia of genes and genomes, and gene ontology analysis. Since the results predicted that some of microRNAs and mRNA may interact with GAPLINC, we simulated a gene co-action network model based on a competitive endogenous RNA theory. Further verification of this model demonstrated that silencing of GAPLINC increased miR-382-5p and miR-575 expression. The results of this study suggest that GAPLINC may function as a novel microRNAs sponging agent affecting the biological characteristics of RA-FLSs. Additionally, GAPLINC may also promote RA-FLS tumor-like behaviors in a miR-382-5p-dependent and miR-575-dependent manner. Based upon these findings, LncRNA GAPLINC may provide a novel valuable therapeutic target for RA patients.

The cohort was set up in order to analyze late effects in long-term testicular cancer survivors (TCS) and to contribute to the design of future follow-up programs addressing and potentially preventing late effects. Data for this cross-sectional study were collected between January 1, 2014, and December 31, 2016, among living Danish TCS and 60% agreed to participate in the cohort (N = 2,572). Mean time since testicular cancer (TC) diagnosis was 18 years (range 7-33) and mean age of participants was 53 years (range 25-95). Data consist of results of a questionnaire with patient reported outcomes which covers a broad range of items on late-effects. The study also included data obtained through linkages to Danish registries, a biobank, and clinical data from hospital files and pathology reports originating from the Danish Testicular Cancer Database (DaTeCa). The treatment during the observation period has been nearly the same for all stages of TC and is in agreement with today's standard treatment, this allows for interesting analysis with a wide timespan. We have extensive data on non-responders and are able to validate our study findings. Data from a Danish reference population (N = 162,283) allow us to compare our findings with a Danish background population. The cohort can easily be extended to access more outcomes, or include new TCS. A limitation of the present study is the cross-sectional design and despite the large sample size, The Danish Testicular Cancer Late Treatment Effects Cohort (DaTeCa-LATE) lacks statistical power to study very rare late effects. Since it was voluntary to participate in the study we have some selection bias, for instance, we lack responders who were not in a paired relationship, but we would still argue that this cohort of TCSs is representative for TCSs in Denmark.Collaboration and data access: Researches interested in collaboration with the DaTeCa-LATE study group please contact Professor Gedske Daugaard kirsten.gedske.daugaard@regionh.dk.

Background: Rheumatoid arthritis (RA) is a progressive, chronic, even disabling systemic autoimmune disease. Imbalance between pathogenic immune cells and immunosuppressive cells is associated with the pathogenesis and development of RA and other autoimmune diseases. As Foxp3 is also expressed on activated CD4 cells in the presence of inflammation, the identification of Treg cells in patients with RA remains a challenge. Methods: Comprehensive analyses were carried out by Flow cytometry. Expression of Helios, CD226, T cell immunoreceptor with Ig and ITIM domains (TIGIT) was analyzed by clinical samples of rheumatoid arthritis patients and healthy controls. Findings: we have systemically examined three potential markers, Helios, CD226 and TIGIT that are possibly related to Treg identification, and found that Helios expression on CD4 Foxp3 cells was decreased and negatively correlated with the disease activity of RA patients, while CD226 and TIGIT both showed elevated expression levels in CD4 Foxp3 cells in RA patients and they were not associated with disease activity of RA patients. Interpretation: Our findings indicate that CD4 CD25hiCD127low/-Foxp3 Helios may represent the real Treg cell population in patients with RA. Funding: This work was supported in part by grants from the National Key R&D Program of China (2017YFA0105800), General Program of National Natural Science Foundation of China (81671611) and the Zhujiang Innovative and Entrepreneurial Talent Team Award of Guangdong Province (2016 ZT 06S 252) and NIH R01 AR 059103. Declaration of Interest: All authors have no conflict of interest. Ethical Approval: All human studies have been approved by the Research Ethical Committee of the Third Affiliated Hospital at Sun Yat-sen University. Before study, written informed consents were received from all participants.

Severe aplastic anemia (AA) is a rare autoimmune disease characterized by severe pancytopenia and bone marrow failure. The recent finding of an abnormal quantity and function of T helper (Th) and regulatory T (Treg) cells in peripheral blood of patients has emerged as the major cause of the condition. Accumulating evidence has revealed that human gingiva-derived mesenchymal stem cells (GMSCs) are emerging as a new line of mesenchymal stem cells may have the potential to control or even treat autoimmune diseases through correcting the balance between Th and Treg cells. Given that GMSCs have a robust immune regulatory function and regenerative ability, we investigated the effect of GMSCs on preventing T cell-mediated bone marrow failure (BMF) in an AA mouse model. We observed that infusion of GMSCs markedly attenuated histological BM damage, controlled immunologically-mediated disorders in AA mice, significantly improved AA mice survival by significantly reducing cell infiltration of both CD8 cells and CD4 T cells (including Th1 and Th17 cells) in lymph nodes and decreased pro-inflammatory cytokines levels in lymph nodes and plasma. Moreover, GMSCs up-regulated the levels of Tregs and increased Foxp3 expression in lymph nodes. Our results demonstrate that the predominant Th1 and Th17 cell infiltration in the AA model could be significantly reduced while Treg cells are increased by GMSCs treatment. Collectively, our data demonstrate that GMSCs can attenuate T cell-mediated bone marrow failure through targeting the balance of Th17 and Treg cells, implicating that the use of GMSCs many have potential clinical application in prevention and treatment of patients with AA. Funding Statement: This study was supported by the National Key R&D Program of China (2017YFA0105800), the National Natural Science Foundation of China (No. 81671611), the Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2016ZT06S252), the National Natural Science Foundation of Guangdong Province (No. 2014A030313131) and NIH R61 AR073409. Declaration of Interests: All authors have no conflict of interest. Ethics Approval Statement: This study was carried out in accordance with the recommendations of the animal use protocol, which was approved by the Institutional Animal Care and Use Committee of Sun Yat-Sen University (Approve number: [2018]02-195-01). Human gingiva samples were collected following routine dental procedures at the Division of Dentistry in the Third Hospital at the Sun Yat-sen University, which were approved by the medical ethics committees of Institutional Review Boards (IRB) at the Third Hospital at the Sun Yat-sen University.

BACKGROUND: Allergic and autoimmune diseases comprise a group of inflammatory disorders caused by aberrant immune responses in which CD25(+) Forkhead box P3-positive (FOXP3(+)) T regulatory (Treg) cells that normally suppress inflammatory events are often poorly functioning. This has stimulated an intensive investigative effort to find ways of increasing Tregs as a method of therapy for these conditions. One such line of investigation includes the study of how ligation of Toll-like receptors (TLRs) by CpG oligonucleotides (ODN) results in an immunostimulatory cascade that leads to induction of T-helper (Th) type 1 and Treg-type immune responses. OBJECTIVE: The present study investigated the mechanisms by which calf thymus mammalian double-stranded DNA (CT-DNA) and a synthetic methylated DNA CpG ODN sequence suppress in vitro lymphoproliferative responses to antigens, mitogens, and alloantigens when measured by [(3)H]-thymidine incorporation and promote FoxP3 expression in human CD4(+) T cells in the presence of transforming growth factor (TGF) beta and interleukin-2 (IL-2). METHODS: Lymphoproliferative responses of peripheral blood mononuclear cells from four healthy subjects or nine subjects with systemic lupus erythematosus to CT-DNA or phytohemagglutinin (PHA) was measured by tritiated thymidine ([(3)H]-TdR) incorporation expressed as a stimulation index. Mechanisms of immunosuppressive effects of CT-DNA were evaluated by measurement of the degree of inhibition to lymphoproliferative responses to streptokinase-streptodornase, phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), or alloantigens by a Con A suppressor assay. The effects of CpG methylation on induction of FoxP3 expression in human T cells were measured by comparing inhibitory responses of synthetic methylated and nonmethylated 8-mer CpG ODN sequences by using cell sorting, in vitro stimulation, and suppressor assay. RESULTS: Here, we showed that CT-DNA and a synthetic methylated DNA 8-mer sequence could suppress antigen-, mitogen-, and alloantigen-induced lymphoproliferation in vitro when measured by [(3)H]-thymidine. The synthetic methylated DNA CpG ODN but not an unmethylated CpG ODN sequence was shown to promote FoxP3 expression in human CD4(+) T cells in the presence of TGF beta and IL-2. The induction of FoxP3(+) suppressor cells is dose dependent and offers a potential clinical therapeutic application in allergic and autoimmune and inflammatory diseases. CONCLUSION: The use of this methylated CpG ODN offers a broad clinical application as a novel therapeutic method for Treg induction and, because of its low cost and small size, should facilitate delivery via nasal, respiratory, gastrointestinal routes, and/or by injection, routes of administration important for vaccine delivery to target sites responsible for respiratory, gastrointestinal, and systemic forms of allergic and autoimmune disease.