Therapeutic advances using targeted biologicals and small-molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell-based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell-based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell-based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders.

• Klíčová slova
• CAR-Treg cells, adoptive cell therapies, allergy, autoimmunity, immunoregulation,
• MeSH
• alergie * terapie   MeSH
• autoimunita MeSH
• autoimunitní nemoci * terapie   MeSH
• bronchiální astma * MeSH
• lidé MeSH
• regulační T-lymfocyty MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Mast cells are powerful immune modulators of the tissue microenvironment. Within seconds of activation, these cells release a variety of preformed biologically active products, followed by a wave of mediator synthesis and secretion. Increasing evidence suggests that an intricate network of inhibitory and activating receptors, specific signaling pathways, and adaptor proteins governs mast cell responsiveness to stimuli. Here, we discuss the biological and clinical relevance of negative and positive signaling modalities that control mast cell activation, with an emphasis on novel FcεRI regulators, immunoglobulin E (IgE)-independent pathways [e.g., Mas-related G protein-coupled receptor X2 (MRGPRX2)], tetraspanins, and the CD300 family of inhibitory and activating receptors.

• MeSH
• antigen Ki-1 metabolismus   MeSH
• degranulace buněk * MeSH
• imunomodulace MeSH
• kationické antimikrobiální peptidy metabolismus   MeSH
• lidé MeSH
• mastocyty imunologie   MeSH
• neuropeptidy metabolismus   MeSH
• proteiny nervové tkáně metabolismus   MeSH
• receptory IgE metabolismus   MeSH
• receptory neuropeptidů metabolismus   MeSH
• receptory spřažené s G-proteiny metabolismus   MeSH
• signální transdukce * MeSH
• spinální ganglia metabolismus   MeSH
• tetraspaniny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• antigen Ki-1 MeSH
• FCER1A protein, human MeSH Prohlížeč
• kationické antimikrobiální peptidy MeSH
• MRGPRX2 protein, human MeSH Prohlížeč
• neuropeptidy MeSH
• proteiny nervové tkáně MeSH
• receptory IgE MeSH
• receptory neuropeptidů MeSH
• receptory spřažené s G-proteiny MeSH
• tetraspaniny MeSH

Mast cells and basophils (MCs/Bs) play a crucial role in type I allergy, as well as in innate and adaptive immune responses. These cells mediate their actions through soluble mediators, some of which are targeted therapeutically by, for example, H1- and H2-antihistamines or cysteinyl leukotriene receptor antagonists. Recently, considerable progress has been made in developing new drugs that target additional MC/B mediators or receptors, such as serine proteinases, histamine 4-receptor, 5-lipoxygenase-activating protein, 15-lipoxygenase-1, prostaglandin D2, and proinflammatory cytokines. Mediator production can be abrogated by the use of inhibitors directed against key intracellular enzymes, some of which have been used in clinical trials (eg, inhibitors of spleen tyrosine kinase, phosphatidylinositol 3-kinase, Bruton tyrosine kinase, and the protein tyrosine kinase KIT). Reduced MC/B function can also be achieved by enhancing Src homology 2 domain-containing inositol 5' phosphatase 1 activity or by blocking sphingosine-1-phosphate. Therapeutic interventions in mast cell-associated diseases potentially include drugs that either block ion channels and adhesion molecules or antagonize antiapoptotic effects on B-cell lymphoma 2 family members. MCs/Bs express high-affinity IgE receptors, and blocking their interactions with IgE has been a prime goal in antiallergic therapy. Surface-activating receptors, such as CD48 and thymic stromal lymphopoietin receptors, as well as inhibitory receptors, such as CD300a, FcγRIIb, and endocannabinoid receptors, hold promising therapeutic possibilities based on preclinical studies. The inhibition of activating receptors might help prevent allergic reactions from developing, although most of the candidate drugs are not sufficiently cell specific. In this review recent advances in the development of novel therapeutics toward different molecules of MCs/Bs are presented.

• Klíčová slova
• Mast cell, basophil, drug, mediator, receptor, signaling protein, survival protein, therapy,
• MeSH
• alergie imunologie   terapie   MeSH
• antialergika farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• bazofily imunologie   MeSH
• cílená molekulární terapie MeSH
• degranulace buněk účinky léků   MeSH
• imunoterapie metody   trendy   MeSH
• iontové kanály antagonisté a inhibitory   MeSH
• lidé MeSH
• mastocyty imunologie   MeSH
• molekuly buněčné adheze antagonisté a inhibitory   MeSH
• receptory IgE antagonisté a inhibitory   MeSH
• receptory kanabinoidní metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antialergika MeSH
• iontové kanály MeSH
• molekuly buněčné adheze MeSH
• receptory IgE MeSH
• receptory kanabinoidní MeSH

Aggregation of the high-affinity IgE receptor (FcεRI) initiates a cascade of signaling events leading to release of preformed inflammatory and allergy mediators and de novo synthesis and secretion of cytokines and other compounds. The first biochemically well defined step of this signaling cascade is tyrosine phosphorylation of the FcεRI subunits by Src family kinase Lyn, followed by recruitment and activation of spleen tyrosine kinase (Syk). Activity of Syk is decisive for the formation of multicomponent signaling assemblies, the signalosomes, in the vicinity of the receptors. Formation of the signalosomes is dependent on the presence of transmembrane adaptor proteins (TRAPs). These proteins are characterized by a short extracellular domain, a single transmembrane domain, and a cytoplasmic tail with various motifs serving as anchors for cytoplasmic signaling molecules. In mast cells five TRAPs have been identified [linker for activation of T cells (LAT), non-T cell activation linker (NTAL), linker for activation of X cells (LAX), phosphoprotein associated with glycosphingolipid-enriched membrane microdomains (PAG), and growth factor receptor-bound protein 2 (Grb2)-binding adaptor protein, transmembrane (GAPT)]; engagement of four of them (LAT, NTAL, LAX, and PAG) in FcεRI signaling has been documented. Here we discuss recent progress in the understanding of how TRAPs affect FcεRI-mediated mast cell signaling. The combined data indicate that individual TRAPs have irreplaceable roles in important signaling events such as calcium response, degranulation, cytokines production, and chemotaxis.

• Klíčová slova
• IgE receptor, LAT/LAT1, LAX, NTAL/Lab/LAT2, PAG/Cbp, mast cells, plasma membrane, transmembrane adaptor proteins,
• Publikační typ
• časopisecké články MeSH