Primary immunodeficiencies (PID) are disorders that for the most part result from mutations in genes involved in immune host defense and immunoregulation. These conditions are characterized by ...various combinations of recurrent infections, autoimmunity, lymphoproliferation, inflammatory manifestations, atopy, and malignancy. Most PID are due to genetic defects that are intrinsic to hematopoietic cells. Therefore, replacement of mutant cells by healthy donor hematopoietic stem cells (HSC) represents a rational therapeutic approach. Full or partial ablation of the recipient's marrow with chemotherapy is often used to allow stable engraftment of donor-derived HSCs, and serotherapy may be added to the conditioning regimen to reduce the risks of graft rejection and graft versus host disease (GVHD). Initially, hematopoietic stem cell transplantation (HSCT) was attempted in patients with severe combined immunodeficiency (SCID) as the only available curative treatment. It was a challenging procedure, associated with elevated rates of morbidity and mortality. Overtime, outcome of HSCT for PID has significantly improved due to availability of high-resolution HLA typing, increased use of alternative donors and new stem cell sources, development of less toxic, reduced-intensity conditioning (RIC) regimens, and cellular engineering techniques for graft manipulation. Early identification of infants affected by SCID, prior to infectious complication, through newborn screening (NBS) programs and prompt genetic diagnosis with Next Generation Sequencing (NGS) techniques, have also ameliorated the outcome of HSCT. In addition, HSCT has been applied to treat a broader range of PID, including disorders of immune dysregulation. Yet, the broad spectrum of clinical and immunological phenotypes associated with PID makes it difficult to define a universal transplant regimen. As such, integration of knowledge between immunologists and transplant specialists is necessary for the development of innovative transplant protocols and to monitor their results during follow-up. Despite the improved outcome observed after HSCT, patients with severe forms of PID still face significant challenges of short and long-term transplant-related complications. To address this issue, novel HSCT strategies are being implemented aiming to improve both survival and long-term quality of life. This article will discuss the current status and latest developments in HSCT for PID, and present data regarding approach and outcome of HSCT in recently described PID, including disorders associated with immune dysregulation.
Inborn errors of immunity are genetic disorders with broad clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation, often leading to multiple ...autoimmune phenomena, lymphoproliferation, and malignancy. The treatment is challenging as it requires careful balancing of immunosuppression in subjects at increased risk of infections. Recently, the improved ability to define inborn errors of immunity pathophysiology at the molecular level has set the basis for the development of targeted therapeutic interventions. Such a "precision medicine" approach is mainly bases on the use of available small molecules and biologics to target a specific cell function. In this article, we summarize the clinical and laboratory features of various recently described inborn errors of immunity associated with immune dysregulation and hyperinflammation in which mechanism-based therapeutic approaches have been implemented.
Introduction: The evolution in immunological methods used to assess human allergic diseases has led to the identification of immunoglobulin E (IgE) as a diagnostic biomarker and a potential ...therapeutic target. Innovative technologies in molecular biology and immunogenetics contributed to the development of a selective blocking agent, disclosing new therapeutic perspectives in the treatment of allergic asthma. Omalizumab is the most advanced humanized anti-IgE monoclonal antibody that specifically binds serum-free IgE. Omalizumab also interrupts the allergic cascade by preventing binding of IgE with FcϵRI receptors on mast cells, basophils, antigen-presenting cells and other inflammatory cells.
Areas covered: This review discusses the discovery strategy and preclinical development of omalizumab. Furthermore, it also provides a clinical overview of the key trials leading to its launch and a detailed analysis of safety and post-marketing data.
Expert opinion: The clinical efficacy of omalizumab in allergic asthma has been well documented in clinical trials, involving adults, adolescents and children with moderate-to-severe and severe allergic asthma. To date, omalizumab has also been approved in chronic idiopathic urticaria for patients 12 years and older who remain symptomatic despite high dosages of H
1
antihistamines. Omalizumab has also been investigated in many other different patient populations beyond allergic asthma and may yet have an application to other indications. While omalizumab is the only mAb available for treating allergic asthma, the authors anticipate that new mAbs will emerge in the future that overcome omalizumab's current limitations.
Severe asthma in children remains a significant issue. It places a heavy burden on affected individuals and society as a whole in terms of high morbidity, mortality, consumption of healthcare ...resources, and side effects from high-dose corticosteroid therapy. New, targeted biologic therapies for asthma have emerged as effective add-on options, complementing our expanding understanding of asthma phenotypes/endotypes and the underlying immunopathology of the disease spectrum. They include omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab. Omalizumab represents the first available therapeutic option for allergic asthma in patients as young as 6 years of age. Its efficacy and safety have been established by several randomized controlled trials specifically conducted in pediatric patients, leading to its final registration > 10 years ago. Three new interleukin (IL)-5 targeted agents, mepolizumab, reslizumab, and benralizumab, have been approved for the treatment of severe eosinophilic asthma starting from 6 years of age, and varying by country. More recently, dupilumab, a targeted agent against the IL-4 receptor α-chain, was approved for patients ≥12 years of age in the United States after pivotal trials were completed. The late-stage clinical testing of these targeted agents has mostly involved patients aged 12 years and up, and the application of those data to younger children can be inappropriate and carry risk. The efficacy and safety of these newer biologics in children should be supported by adequate research within this targeted age group. In this review, we will present the most recent evidence on these five biological therapies for severe asthma and will discuss dosage and administration, their efficacy, safety, and future prospects, with a focus on the pediatric age group, defined as age < 18 years.
Atopic dermatitis (AD) is a condition with a multifactorial aetiology that affects the skin. It most often begins at preschool age and involves the skin. The disease's main symptom is intense ...itching, which occurs especially at night and affects the child's sleep, negatively impacting the quality of life of affected children and, consequently, their families. The difficulty in resting during the night leads to many problems during the day, particularly behavioural disorders and difficulties in paying attention at school, which results in learning impairment. The unexpected symptoms of AD are caused by pathophysiological processes that include many molecular pathways and inflammatory cytokines such as IL-31, IL-1, IL-2, TNF-a, and IL-6. Drawing on a comprehensive review of the literature in PubMed/MedLine, our review offers an in-depth exploration of both the psychosocial impacts of AD and the molecular processes that contribute to this disorder.
Oral immunotherapy in pediatrics Arasi, Stefania; Castagnoli, Riccardo; Pajno, Giovanni B.
Pediatric allergy and immunology,
February 2020, 2020-02-00, 20200201, Letnik:
31, Številka:
S24
Journal Article
Recenzirano
IgE‐mediated food allergy (FA) has been emerging as a public health priority, mainly in children. It represents a heavy burden for the entire society and not only for the patients and their families. ...There is evidence that in children with persistent FA, at least to cow's milk, hen's egg, and peanut, oral immunotherapy (OIT) may increase the reaction threshold to food allergen(s), while receiving active therapy (the so‐called “desensitization”). Furthermore, OIT protects patients from the occurrence of severe reactions in the event of accidental ingestion of the culprit food during treatment. However, many gaps are still unsolved, including safety issues, identification of predictive biomarkers, and post‐desensitization efficacy. This article briefly summarizes the current evidence and the main needs in OIT to stimulate the development of longitudinal, prospective, well‐designed studies able to fill the current gaps soon.
Inborn errors of immunity (IEI) are a group of disorders that are mostly caused by genetic mutations affecting immune host defense and immune regulation. Although IEI present with a wide spectrum of ...clinical features, in about one third of them various degrees of gastrointestinal (GI) involvement have been described and for some IEI the GI manifestations represent the main and peculiar clinical feature. The microbiome plays critical roles in the education and function of the host's innate and adaptive immune system, and imbalances in microbiota-immunity interactions can contribute to intestinal pathogenesis. Microbial dysbiosis combined to the impairment of immunosurveillance and immune dysfunction in IEI, may favor mucosal permeability and lead to inflammation. Here we review how immune homeostasis between commensals and the host is established in the gut, and how these mechanisms can be disrupted in the context of primary immunodeficiencies. Additionally, we highlight key aspects of the first studies on gut microbiome in patients affected by IEI and discuss how gut microbiome could be harnessed as a therapeutic approach in these diseases.
Biological therapies targeting specific cytokines and receptors provide successful treatment options for pediatric patients with allergic diseases. Defining their indications, dosing, and safety ...profiles is essential for optimizing outcomes and improving the quality of life for children with allergic chronic conditions.
This paper investigates the electrochemical properties of a new Cu(II)-based metal-organic framework (MOF). Noted as Cu-YBDC, it is built upon a linker containing the propargyl carbamate ...functionality and immobilized on a glassy carbon electrode by drop-casting (GC/Cu-YBDC). Afterward, GC/Cu-YBDC was treated with HAuCl
and the direct electro-deposition of Au nanoparticles was carried at 0.05 V for 600 s (GC/Au/Cu-YBDC). The performance of both electrodes towards nitrite oxidation was tested and it was found that GC/Au/Cu-YBDC exhibited a better electrocatalytic behavior toward the oxidation of nitrite than GC/Cu-YBDC with enhanced catalytic currents and a reduced nitrite overpotential from 1.20 to 0.90 V. Additionally GC/Au/Cu-YBDC showed a low limit of detection (5.0 μM), an ultrafast response time (<2 s), and a wide linear range of up to 8 mM in neutral pH.
Introduction: Severe asthma is a complex heterogeneous disease that is refractory to standard treatment and is complicated by multiple co-morbidities and risk factors. Several co-morbidities may ...contribute to worsen asthma control and complicate diagnostic and therapeutic management of severe asthmatic patients.
Areas covered: A prevalent cluster of chronic upper airway co-morbid diseases is recognized in severe asthma. Evaluation for these disorders should always be considered in clinical practice. The aim of this review is to provide an updated overview of the prevalence, the pathogenetic mechanisms, the clinical impact and the therapeutic options for upper airway pathology in severe asthma, focusing on chronic rhinosinusitis and allergic rhinitis.
Expert commentary: In the context of severe asthma, the clinical significance of upper airway co-morbidities is based on mutual interactions complicating diagnosis and management. A better analysis and understanding of phenotypes and endotypes of both upper and lower airway diseases are crucial to further develop targeted treatment.
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