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Zinc and vitamin C intake increases spike and neutralising antibody production following SARS-CoV-2 infection.
Quek, AML, Ooi, DSQ, Teng, O, Chan, CY, Ng, GJL, Ng, MY, Yee, S, Cheong, EW, Weng, R, Cook, AR, et al
Clinical and translational medicine. 2022;(2):e731
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Incidence, Risk Factors, and Outcome of Immune-Mediated Neuropathies (IMNs) following Haploidentical Hematopoietic Stem Cell Transplantation.
Ren, XY, Liu, X, Huang, QS, Wang, QM, He, Y, Zhu, XL, Han, W, Chen, H, Chen, YH, Wang, FR, et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019;(8):1629-1636
Abstract
Immune-mediated neuropathies (IMNs) following hematopoietic stem cell transplantation have been described recently, which, excluding Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, may present with atypical patterns. This retrospective, nested, case-control study reviewed data from 3858 patients who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) during the past 10 years at a single center, and 40 patients (1.04%) with IMN following haplo-HSCT were identified. Chronic graft-versus-host disease (cGVHD) (P = .043) and cytomegalovirus (CMV) viremia (P = .035) were recognized as independent risk factors for the development of IMN after haplo-HSCT. There were no significant differences in overall survival (P = .619), disease-free survival (P = .609), nonrelapse mortality (P = .87), or the incidence of relapse (P = .583) between patients with and without IMN after haplo-HSCT. However, patients with post-transplant IMN were at higher risk of developing cGVHD (P = .012) than patients who did not develop IMN. Twenty-four of the 40 patients with IMN (60%) attained neurologic improvement after treatments including vitamins B1 and B12 and/or immunomodulatory agents. However, 19 (47.5%) patients still had persistent motor/sensory deficits despite receiving timely treatment. More studies are needed to help develop standardized diagnostic and therapeutic strategies for patients with post-transplant IMN.
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Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.
Imel, EA, Glorieux, FH, Whyte, MP, Munns, CF, Ward, LM, Nilsson, O, Simmons, JH, Padidela, R, Namba, N, Cheong, HI, et al
Lancet (London, England). 2019;(10189):2416-2427
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Abstract
BACKGROUND X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. METHODS In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. FINDINGS Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. INTERPRETATION Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. FUNDING Ultragenyx Pharmaceutical and Kyowa Kirin International.
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The Footprints of Poly-Autoimmunity: Evidence for Common Biological Factors Involved in Multiple Sclerosis and Hashimoto's Thyroiditis.
Perga, S, Martire, S, Montarolo, F, Giordani, I, Spadaro, M, Bono, G, Corvisieri, S, Messuti, I, Panzica, G, Orlandi, F, et al
Frontiers in immunology. 2018;:311
Abstract
Autoimmune diseases are a diverse group of chronic disorders and affect a multitude of organs and systems. However, the existence of common pathophysiological mechanisms is hypothesized and reports of shared risk are emerging as well. In this regard, patients with multiple sclerosis (MS) have been shown to have an increased susceptibility to develop chronic autoimmune thyroid diseases, in particular Hashimoto's thyroiditis (HT), suggesting an autoimmune predisposition. However, studies comparing such different pathologies of autoimmune origin are still missing till date. In the present study, we sought to investigate mechanisms which may lead to the frequent coexistence of MS and HT by analyzing several factors related to the pathogenesis of MS and HT in patients affected by one or both diseases, as well as in healthy donors. In particular, we analyzed peripheral blood mononuclear cell gene-expression levels of common candidate genes such as TNFAIP3, NR4A family, BACH2, FOXP3, and PDCD5, in addition to the regulatory T cell (Treg) percentage and the 25-hydroxy vitamin D serum levels. Our findings support the plausibility of the existence of common deregulated mechanisms shared by MS and HT, such as BACH2/PDCD5-FOXP3 pathways and Tregs. Although the biological implications of these data need to be further investigated, we have highlighted the relevance of studies comparing different autoimmune pathologies for the understanding of the core concepts of autoimmunity.
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Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS.
Ziemssen, T, Tumani, H, Sehr, T, Thomas, K, Paul, F, Richter, N, Samara, E, Spiegelstein, O, Sorani, E, Bar-Ilan, O, et al
Journal of neuroinflammation. 2017;(1):172
Abstract
BACKGROUND Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of laquinimod in patients with RRMS. METHODS One hundred twelve patients were randomly assigned to laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments. RESULTS Twenty-eight patients received placebo and 84 received laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following laquinimod compared to placebo. CONCLUSION Laquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of laquinimod on the innate immune system was demonstrated. TRIAL REGISTRATION EudraCT Number: 2009-011234-99 . Registered 23 June 2009.
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A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease.
Ostrowitzki, S, Lasser, RA, Dorflinger, E, Scheltens, P, Barkhof, F, Nikolcheva, T, Ashford, E, Retout, S, Hofmann, C, Delmar, P, et al
Alzheimer's research & therapy. 2017;(1):95
Abstract
BACKGROUND Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer's disease (AD). METHODS In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. RESULTS Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. CONCLUSIONS The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy. TRIAL REGISTRATION ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.
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A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection.
Lachmann, R, Bevan, MA, Kim, S, Patel, N, Hawrylowicz, C, Vyakarnam, A, Peters, BS
AIDS (London, England). 2015;(10):1127-35
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OBJECTIVES To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity. DESIGN This was a pilot, open-label, three-arm prospective phase 1 study. METHODS We recruited 28 patients with low plasma vitamin D (<50 nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200 000 IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4 T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation. RESULTS One month of vitamin D supplementation restored plasma levels to sufficiency (>75 nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1β - an important anti-HIV blocking chemokine - were observed, with a concomitant increase in plasma MIP-1β, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin - a vitamin D response gene with broad antimicrobial activity - was enhanced. CONCLUSION Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy.
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Efficacy of Rituximab in Refractory Inflammatory Myopathies Associated with Anti- Synthetase Auto-Antibodies: An Open-Label, Phase II Trial.
Allenbach, Y, Guiguet, M, Rigolet, A, Marie, I, Hachulla, E, Drouot, L, Jouen, F, Jacquot, S, Mariampillai, K, Musset, L, et al
PloS one. 2015;(11):e0133702
Abstract
OBJECTIVE Anti-synthetase syndrome (anti-SS) is frequently associated with myositis and interstitial lung disease (ILD). We evaluated prospectively, in a multicenter, open-label, phase II study, the efficacy of rituximab on muscle and lung outcomes. METHODS Patients were enrolled if they were refractory to conventional treatments (prednisone and at least 2 immunosuppressants). They received 1 g of rituximab at D0, D15, and M6. The primary endpoint was muscular improvement based on manual muscular testing (MMT10, Kendall score in 10 muscles) at M12. Secondary endpoints were normalization of creatine kinase (CK) level, ILD improvement based on forced vital capacity and/or diffuse capacity for carbon monoxide, and number and/or doses of associated immunosuppressants. RESULTS Twelve patients were enrolled, and 10 completed the study. Only 2 patients presented an improvement of at least 4 points on at least two muscle groups (primary end-point). Overall, seven patients had an increase of at least 4 points on MMT10. CK level decreased from 399 IU/L (range, 48-11,718) to 74.5 IU/L (range, 40-47,857). Corticosteroid doses decreased from 52.5 mg/d (range, 10-70) to 9 mg/d (range, 7-65) and six patients had a decrease in the burden of their associated immunosuppressants. At baseline, all 10 patients presented with ILD. At M12, improvement of ILD was observed in 5 out of the 10 patients, stabilization in 4, and worsening in 1. CONCLUSIONS This pilot study of rituximab treatment in patients with refractory anti-SS provided data on evolution of muscular and pulmonary parameters. Rituximab should now be evaluated in a larger, controlled study for this homogenous group of patients. TRIAL REGISTRATION Clinicaltrials.gov NCT00774462.
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Soluble Immune Mediators and Vaginal Bacteria Impact Innate Genital Mucosal Antimicrobial Activity in Young Women.
Pellett Madan, R, Dezzutti, CS, Rabe, L, Hillier, SL, Marrazzo, J, McGowan, I, Richardson, BA, Herold, BC, ,
American journal of reproductive immunology (New York, N.Y. : 1989). 2015;(4):323-32
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INTRODUCTION Innate activity against Escherichia coli in female genital secretions may represent contributions from vaginal bacteria and host soluble immune mediators. We analyzed the relationship between E. coli inhibitory activity, soluble immune mediators, and vaginal bacteria in participants in MTN-004, a placebo-controlled trial of VivaGel(®) , a candidate product for topical HIV pre-exposure prophylaxis. METHODS Escherichia coli inhibitory activity was quantified by colony reduction assay. Endocervical concentrations of interleukin (IL)-1β, IL-6, IL-12p40, macrophage inflammatory protein (MIP)-1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), lactoferrin, and secretory leukocyte protease inhibitor (SLPI) were quantified to generate a cumulative mediator score. Vaginal bacteria were characterized by quantitative cultures. RESULTS In the two placebo arms, higher soluble immune mediator score was associated with greater E. coli inhibitory activity (β = 17.49, 95% CI [12.77, 22.21] and β = 13.28, 95% CI [4.76, 21.80]). However, in the VivaGel arm, higher concentrations of E. coli (β = -3.80, 95% CI [-6.36, -1.25]) and group B Streptococcus (β = -3.91, 95% CI [-6.21, -1.60]) were associated with reduced E. coli inhibitory activity. CONCLUSIONS Both host mediators and vaginal bacteria impact E. coli inhibition in genital secretions. The relative contributions of host mediators and bacteria varied between women who used VivaGel vs placebos.
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Antioxidant bioavailability and rapid immune-modulating effects after consumption of a single acute dose of a high-metabolite yeast immunogen: results of a placebo-controlled double-blinded crossover pilot study.
Jensen, GS, Redman, KA, Benson, KF, Carter, SG, Mitzner, MA, Reeves, S, Robinson, L
Journal of medicinal food. 2011;(9):1002-10
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Abstract
The objective of this pilot study was to investigate the acute effects on circulating lymphocyte subsets, antioxidant status, and cytokine profile after consumption of EpiCor(®) (EP) (Embria Health Sciences, Ankeny, IA, USA), a dried fermentate produced from Saccharomyces cerevisiae, using a placebo-controlled randomized crossover study design with 12 healthy adult human subjects. EP contains high levels of bioavailable antioxidants and strongly activates natural killer (NK) cells in vitro. EP consumption has been shown to increase erythrocyte hematocrit levels, boost mucosal immune protection, reduce cold/flu symptoms, reduce seasonal allergy symptoms and the need for rescue medication, and increase salivary secretory immunoglobulin A levels. This warranted further study on immune effects in humans. A within-subject analysis of data collected before and at 1 and 2 hours after consumption of a single dose of 500 mg of EP versus placebo was performed. A transient reduction in circulating T and NK cell numbers was observed 2 hours post-consumption, suggesting that homing and recirculation of these cells, as part of healthy immune surveillance, were supported by EP. The increased expression of activation markers on the CD3(-) CD56(+) NK cell population was significant for CD69 at 1 hour post-consumption (CD25, P<.07; CD69, P<.05), whereas for CD25 it was significant at 2 hours after consumption (CD25, P<.03; CD69, P<.15). A rapid increase in serum interferon-γ was observed at 1 hour post-consumption (P<.07; after removal of two outlying data sets, P<.05) and may have contributed to the effects seen on NK and T cell subsets. Significant increase in serum antioxidant protection was seen 2 hours after consumption (P<.04). Thus consumption of a single 500 mg dose of EP provides a rapid and transient effect on the trafficking and activation status of specific lymphocyte subsets, as well as increased antioxidant protection.