Výběr biologik u pacientů s těžkým astmatem vychází z diagnostického posouzení, zda se jedná o T2-high (tj. eozinofilní, alergický či nealergický), nebo T2-low (tj. non- -eozinofilní) zánětlivý endotyp/fenotyp astmatu. V současnosti jsou dostupné tři molekuly s antieozinofilním přístupem do dráhy interleukinu-5 (mepolizumab, benralizumab, reslizumab), molekula zaměřená na receptor pro IL-4/13 (dupilumab) a molekula s vazbou na IgE (omalizumab). Konceptem je cesta zaměřená vůči epiteliálním alarminům („upstream“ cytokiny). Poslední molekulou, která vstoupila do klinické praxe, je tezepelumab blokující thymický stromální lymfopoetin. Účinnost tezepelumabu je dokladována u široké populace astmatiků napříč spektrem etiologií exacerbací. Bylo prokázáno, že tezepelumab snižuje výskyt exacerbací a hladiny biomarkerů (absolutní počet eozinofilů, celkový IgE, FeNO) bez ohledu na výchozí hodnotu BMI, roční období nebo stav atopie. Blokáda epiteliálních alarminů je nadějí i pro astmatiky s T2-low typem zánětu. Zkoumány jsou další antialarminové molekuly, slibný je itepekimab působící vůči IL-33. Zcela novým budoucím směrem v léčbě T2-high astmatu se jeví selektivní inhibitory Brutonovy tyrosinkinázy (například rilzabrutinib), které inhibují dráhu FcεRI v mastocytech a bazofilech, a mohou tak ovlivňovat tíži eozinofilního zánětu.
The choice of biologics in patients with severe asthma is based on the diagnostic assessment of whether it is T2-high (i.e. eosinophilic, allergic or non-allergic) or T2-low (i.e. non-eosinophilic) inflammatory endotype/phenotype of asthma. Currently, three molecules with anti-eosinophilic access to the interleukin-5 pathway (mepolizumab, benralizumab, reslizumab), a molecule targeting the receptor for IL4/13 (dupilumab), and a molecule with binding to IgE (omalizumab) are available. A novel concept is the pathway directed towards epithelial alarmins ("upstream" cytokines). A molecule that has recently entered clinical practice is tezepelumab blocking thymic stromal lymphopoietin. The efficacy of tezepelumab has been documented in a wide population of asthmatics across the spectrum of exacerbation etiologies. Tezepelumab was shown to reduce exacerbations rate and biomarker levels (absolute eosinophil count, total IgE, FeNO) regardless of baseline BMI, season or atopy status. Blocking epithelial alarmins is also a hope for asthmatics with T2-low type of inflammation. There are other antialarmin molecules being investigated, itepecimab is promising against interleukin-33. A completely new future direction in the treatment of T2-high asthma appears to be selective Bruton's tyrosine kinase inhibitors (e.g. rilzabrutinib), which inhibit the FcεRI pathway in mast cells and basophils and can thus influence the severity of eosinophilic inflammation.
OBJECTIVES: Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis. METHODS: The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing). RESULTS: Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-β/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc. CONCLUSION: Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc.
- MeSH
- Alarmins * MeSH
- Bleomycin toxicity MeSH
- Fibrosis MeSH
- Skin * pathology MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Antibodies, Monoclonal pharmacology MeSH
- Mice MeSH
- S100 Calcium-Binding Protein A4 genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Biologická léčba je nadějí pro těžké astmatiky a jsou očekávána další biologika ve fázích klinických zkoušek cílená na typy respiračního zánětu. Výběr biologik u pacientů s těžkým astmatem vychází z diagnostického posouzení, zda se jedná o T2-high (tj. eozinofilní, alergický či nealergický) anebo T2-low (t. j. noneozinofilní) zánětlivý endotyp/fenotyp astmatu. V klinické praxi máme dostupné tři molekuly s antieozinofilním přístupem do dráhy cytokinu 5 (mepolizumab, benralizumab, reslizumab), molekulu zaměřenou na receptor pro IL4/13 (dupilumab), molekulu s vazbou na imunoglobulin E (omalizumab). Poslední molekulou, která vstoupila do klinické praxe, je tezepelumab blokující cytokin ze skupiny epiteliálních alarminů - thymický stromální lymfopoetin. Inhibice alarminů ("upstream" cytokinů) je novým konceptem cytokinové blokace. Studovány jsou další molekuly určené k inhibici alarminových drah, z nichž jako slibný se jeví anti‐IL33 itepekimab. Blokace epiteliálních alarminů může být i perspektivou pro astmatiky s T2-low typem zánětu, kde účinné biologikum zatím chybí.
Biological therapy shows promise for patients with severe asthma, and more biological drugs in clinical trial phases targeted at types of airway inflammation are expected. The choice of biologicals in patients with severe asthma is based on a diagnostic assessment of whether the inflammatory asthma endotype/phenotype is T2-high (i.e., eosinophilic, allergic, or non-allergic) or T2-low (i.e., non-eosinophilic). In clinical practice, three molecules with an anti-eosinophilic access to the cytokine 5 pathway (mepolizumab, benralizumab, reslizumab), a molecule targeted at the IL4/13 receptor (dupilumab), and a molecule binding to immunoglobulin E (omalizumab) are available. The latest molecule to have been introduced in clinical practice is tezepelumab that blocks thymic stromal lymphopoietin, an epithelial alarmin cytokine. Inhibition of alarmins (upstream cytokines) is a novel concept of cytokine blockade. Other molecules intended to inhibit alarmin pathways are also being studied, among which anti‐IL33 itepekimab shows promise. Blockade of epithelial alarmins can be promising for asthma patients with the T2-low type inflammation where an effective biological drug is lacking.
- Keywords
- tezepelumab, brodalumab, itepekimab,
- MeSH
- Alarmins antagonists & inhibitors MeSH
- Biological Therapy methods MeSH
- Asthma * drug therapy immunology physiopathology MeSH
- Antibodies, Monoclonal, Humanized administration & dosage pharmacology therapeutic use MeSH
- Interleukins antagonists & inhibitors MeSH
- Clinical Studies as Topic MeSH
- Humans MeSH
- Thymic Stromal Lymphopoietin antagonists & inhibitors immunology MeSH
- Check Tag
- Humans MeSH
Surgery is associated with alterations of alarmins' and related molecules' levels. The aim of this study was to investigate which biomarkers are most involved in surgery. The studied group consisted of 58 patients with inguinal or umbilical hernia or cholecystolithiasis and 21 healthy controls for compa-rison. We also added seven acute patients with appendicitis, cholecystitis and incarcerated hernia. Serum concentrations of soluble receptor of advanced glycation end-products (sRAGE), extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE), calprotectin, high mobility group box 1 (HMGB1) and interleukin 6 (IL-6) were analysed by ELISA before and after surgery. Preoperative concentrations of calprotectin were significantly decreased while concentrations of sRAGE were significantly increased in patients compared to controls; the concentrations of EN-RAGE and HMGB1 did not differ significantly. IL-6 levels were undetectable in elective patients preoperatively and in controls. Postoperatively, there was a significant increase of EN-RAGE, calprotectin, HMGB1, and IL-6 and a significant decrease of sRAGE compared to preoperative levels. In acute patients, all tested molecules except for sRAGE were significantly increased preoperatively, and sRAGE was significantly decreased. In contrast, after surgery, we could observe a further increase in IL-6; the other biomarkers did not differ significantly. We can conclude that the concentrations of all tested biomarkers are significantly influenced by elective surgery. The postoperative levels of all tested molecules increase except for sRAGE, whose level is significantly decreased after surgery. In acute states, these molecules are already increased, and the influence of surgery is, apart from IL-6, insignificant.
- MeSH
- Alarmins * MeSH
- Biomarkers MeSH
- Interleukin-6 metabolism MeSH
- Leukocyte L1 Antigen Complex MeSH
- Humans MeSH
- Glycation End Products, Advanced MeSH
- HMGB1 Protein * metabolism MeSH
- Receptor for Advanced Glycation End Products metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Vo svojej podstate bronchiálna astma je charakterizovaná vysokou heterogenitou klinických príznakov, variabilným klinickým priebehom a rozličnou klinickou odpoveďou na terapeutickú intervenciu. Simplexná nozologická predloha choroby ako jednej klinicky uniformnej jednotky bola nahradená podstatne zložitejším pohľadom na komplex biologickej siete odlišných a vzájomne prepojených zápalových dráh. Preto s cieľom lepšieho a podrobnejšieho oboznámenia s podstatou ochorenia je snaha o čo najlepšiu identifikáciu jednotlivých patologických kaskád na molekulárnej úrovni a ich vzájomných interakcií s mikroprostredím dýchacích ciest – endotypy astmy. Identifikácia jednotlivých molekulárnych zložiek zápalových procesov vedie k možnosti vývoja inovatívnej a cielenej liečby modulujúcej tieto patologické pochody. Dôslednou endotypizáciou najmä závažnej, ťažko liečiteľnej astmy vieme identifikovať potenciálne ciele biologickej liečby k zvráteniu nepriaznivého priebehu ochorenia a tým zlepšeniu kvality života postihnutých pacientov.
Bronchial asthma is inherently characterized by a high heterogeneity of clinical symptoms, variable clinical course and different clinical response to therapeutic intervention. The simplex nosological model of the disease as a single clinically uniform entity has been replaced by a considerably more complex view of biological network of distinct and interrelated inflammatory pathways. Furthermore, with aim of reaching better knowledge of disease, there is an effort for better understanding pathological pathways on molecular base and their interactions with airways microbiome - endotypes of asthma. Identification of individual molecular components of inflammation processes leads to development of innovative biologicals to stop these pathological cascades. Consistent work with endotyping especially severe and difficult to treat asthma can distinguish potential targets for biological treatment to revert unfavorable course of the disease and improve quality of life of affected patients.
- MeSH
- Alarmins physiology immunology MeSH
- Asthma * diagnosis etiology classification MeSH
- Immunity, Cellular immunology MeSH
- Dendritic Cells MeSH
- Child MeSH
- Adrenal Cortex Hormones therapeutic use MeSH
- Interleukins immunology MeSH
- Humans MeSH
- Adolescent MeSH
- Th2 Cells MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Publication type
- Review MeSH
BACKGROUND: Psoriasis is a chronic systemic inflammatory disease with (extra-)cutaneous manifestations. Inflammation is associated with cellular stress and tissue damage which lead to the release of alarmins (signals of danger). Goeckerman regimen (GR) is a highly efficacious treatment consisting of the application of pharmaceutical crude tar and UVB light exposure. The reduction of inflammatory processes in the skin is accompanied by changes in the levels of inflammatory markers - alarmins (HMBG-1, S100A7, S1000A8, S100A9, S100A12, IL-17, IL-22, and IL-33). METHODS: The alarmin levels in sera of 19 paediatric patients with psoriasis were determined before and after GR using commercial ELISA kits. The Psoriasis area severity index (PASI) was used to determine the disease severity. RESULTS: GR reduced both PASI and the levels of all measured alarmins. The levels of S100A7, S100A9, IL-22, IL-33, and HMGB-1 were significantly decreased. Positive correlations between IL-22 and PASI, between S100A9 and IL-17, S100A9 and IL-22, and a negative correlation between S100A8 and IL-33 were found. CONCLUSIONS: Goeckerman regimen is a very effective, safe and low-cost therapy. We confirmed, it modulates the immune system reactivity, ameliorates the severity of the disease and reduces the levels of alarmins reflecting the presence and intensity of inflammation.
- MeSH
- Alarmins MeSH
- Biomarkers MeSH
- Coal Tar * therapeutic use MeSH
- Child MeSH
- Humans MeSH
- Psoriasis * drug therapy MeSH
- Severity of Illness Index MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
In some settings, cancer cells responding to treatment undergo an immunogenic form of cell death that is associated with the abundant emission of danger signals in the form of damage-associated molecular patterns. Accumulating preclinical and clinical evidence indicates that danger signals play a crucial role in the (re-)activation of antitumor immune responses in vivo, thus having a major impact on patient prognosis. We have previously demonstrated that the presence of calreticulin on the surface of malignant blasts is a positive prognostic biomarker for patients with acute myeloid leukemia (AML). Calreticulin exposure not only correlated with enhanced T-cell-dependent antitumor immunity in this setting but also affected the number of circulating natural killer (NK) cells upon restoration of normal hematopoiesis. Here, we report that calreticulin exposure on malignant blasts is associated with enhanced NK cell cytotoxic and secretory functions, both in AML patients and in vivo in mice. The ability of calreticulin to stimulate NK-cells relies on CD11c+CD14high cells that, upon exposure to CRT, express higher levels of IL-15Rα, maturation markers (CD86 and HLA-DR) and CCR7. CRT exposure on malignant blasts also correlates with the upregulation of genes coding for type I interferon. This suggests that CD11c+CD14high cells have increased capacity to migrate to secondary lymphoid organs, where can efficiently deliver stimulatory signals (IL-15Rα/IL-15) to NK cells. These findings delineate a multipronged, clinically relevant mechanism whereby surface-exposed calreticulin favors NK-cell activation in AML patients.
- MeSH
- Lymphocyte Activation MeSH
- Leukemia, Myeloid, Acute * therapy MeSH
- Killer Cells, Natural MeSH
- Cytotoxicity, Immunologic MeSH
- Interleukin-15 MeSH
- Calreticulin * genetics metabolism MeSH
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Immunogenic cell death (ICD), a functionally peculiar type of apoptosis, represents a unique way to deliver danger-associated molecular patterns (DAMPs) to the tumor microenvironment. Once emitted by dying cancer cells, DAMPs orchestrate antigen-specific immune responses by acting on both innate and adaptive components of the immune system. Accumulating preclinical and clinical evidence indicates that one of these DAMPs, calreticulin (CALR) represents a novel powerful prognostic biomarker, reflecting the activation of a clinically relevant anticancer immune response in different cancer malignancies. Therefore, the assessment of CALR emission can provide a therapeutic tool for the stratification of cancer patients and the identification of individuals that are intrinsically capable to respond to a particular treatment. Here we describe methods for the quantification of CALR exposure in the tumor microenvironment of cancer patients by flow cytometry and immunohistochemistry.
- MeSH
- Immunogenic Cell Death * MeSH
- Immunohistochemistry methods MeSH
- Calreticulin analysis immunology MeSH
- Humans MeSH
- Biomarkers, Tumor analysis immunology MeSH
- Tumor Microenvironment MeSH
- Neoplasms immunology pathology MeSH
- Flow Cytometry methods MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
Background: Psoriasis vulgaris is a chronic autoimmune disease associated with systemic inflammation. Increased levels of numerous cytokines, chemokines, growth factors, and other molecules were found in the skin and in the circulation of psoriatic patients. Alarmins, also known as danger signals, are intracellular proteins, which are released to an extracellular space after infection or damage. They are the markers of cell destructive processes. Objective: The aim of the present study was to evaluate the suitability of selected alarmins (HMGB1, IL-33, S100A7, and S100A12) as potential biomarkers of severity of psoriasis and to explore possible relationships between these proteins for the purpose of better understanding their roles in the immunopathology of psoriasis. Methods: The serum levels of selected alarmins were measured in 63 psoriatic patients and 95 control individuals. The levels were assessed by the ELISA technique using commercial kits. The data were statistically processed with MedCalc version 19.0.5. Results: In psoriatic patients, we found significantly increased levels of HMGB1 (p < 0.05), IL-33 (p < 0.01), S100A7 (p < 0.0001), and S100A12 (p < 0.0001). In addition, we found a significant relationship between HMGB1 and S100A7 (Spearman's rho = 0.276, p < 0.05) in the patients and significant relationship between HMGB1 and IL-33 in the controls (Spearman's rho = 0.416, p < 0.05). We did not find any relationship between observed alarmins and the disease severity. Conclusions: The alarmins HMGB1, IL-33, S100A7, and S100A12 were significantly elevated in the serum of patients, which states the hypothesis that they play specific roles in the immunopathology of psoriasis. However, we have not yet found a relationship between observed alarmins and the disease severity. The discovery of the relationship between HMGB1 and S100A7 is a novelty that should be studied in the future to further clarify its role and importance.
- MeSH
- Alarmins blood MeSH
- Adult MeSH
- Interleukin-33 blood MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- HMGB1 Protein blood MeSH
- S100A12 Protein blood MeSH
- S100 Calcium Binding Protein A7 blood MeSH
- Psoriasis immunology MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Severity of Illness Index MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Over the past two decades, a major goal of our research group has been elucidation of the functional roles of several key regulatory molecules in proinflammatory preconditioning involved in the pathophysiology of seemingly diverse human disease states. By necessity, operational definitions of proinflammation must be intrinsically fluid based on recent advances in our understanding of complex regulation of innate and adaptive immune processes. Similar to systemic acute stress, a physiological proinflammatory state appears to be a key autoregulatory mechanism for maintaining optimal immune surveillance against potentially infective microorganisms, viruses, and toxic xenobiotics. Perturbation of normative biochemical and molecular mosaics of ongoing proinflammatory tone, exemplified by altered expression of pro- and anti-inflammatory cytokines and their respective protein complexes, is hypothesized to be a common modality for initiation and full expression of various autoimmune diseases and comorbid syndromes evolving from metabolic and metastatic diseases. The newly reported presence of "free" (extracellular) mitochondria exponentially adds to our hypothesis that in conditions of acute stress, a new source of potential ATP producers may be recruited and present to deal with such an acute process. Furthermore, given this phenomenon, an early surveillance role and a dysfunctional chronic inflammation-prolonging component may also be surmised.
- MeSH
- Alarmins immunology metabolism MeSH
- Anti-Inflammatory Agents metabolism MeSH
- Autoimmune Diseases blood immunology MeSH
- Extracellular Space immunology metabolism MeSH
- Humans MeSH
- Inflammation Mediators metabolism MeSH
- Mitochondria immunology metabolism MeSH
- Mitophagy immunology MeSH
- Inflammation blood immunology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Editorial MeSH
