ABSTRACT
BACKGROUND: Anti-IgE therapy with omalizumab is an innovative therapy option in patients with severe allergic asthma. However, many patients are excluded from this treatment due to very high serum IgE levels which lie above the weight-dependent cut-off for a reasonable omalizumab administration (700 kU/l). OBJECTIVE: We sought to evaluate whether a preceding plasma exchange is suitable to establish the starting basis for a subsequent anti-IgE therapy in a 15 year-old boy with steroid-resistant unstable allergic asthma whose pretreatment serum IgE levels ranged between 3 000 and 8 000 kU/l. METHODS: Our aim was to create a period with relatively low IgE serum concentrations, which could be overridden by a high dose of omalizumab. 3 sessions of plasmapheresis were performed and 3×3 000 ml plasma were exchanged against albumin solution. RESULTS: We removed an absolute amount of 8 650 kU total IgE. During plasmapheresis, serum IgE levels markedly declined and fell below 500 kU/l. Immediately after the third plasma exchange, we started omalizumab therapy. As expected, total IgE levels began to rise again upon cessation of plasmapheresis, and after 2 months the pre-treatment values were reached. In contrast, serum concentrations of free IgE remained stable on a level of about 80 kU/l during the whole observation period. During this period, the boy displayed a considerable improvement of asthma control and an increase in quality of life. In addition, his previously poor lung function normalized. CONCLUSIONS: Plasmapheresis prior to omalizumab administration is suitable to temporarily reduce grossly elevated serum IgE levels and might facilitate anti-IgE therapy in selected patients previously considered not suitable for this therapy.
Subject(s)
Anti-Asthmatic Agents/administration & dosage , Antibodies, Anti-Idiotypic/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Asthma/immunology , Asthma/therapy , Immunoglobulin E/blood , Plasmapheresis , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/therapy , Adolescent , Body Weight , Combined Modality Therapy , Follow-Up Studies , Humans , Male , Omalizumab , Reference ValuesABSTRACT
BACKGROUND: When bound to mast cell FcepsilonRI, IgE serves as antigen receptor for allergic reactions, permitting specific identification of the allergen. Although the core of the classic antigen-binding site is heavy chain complementarity determining region 3 (CDR-H3), recent studies suggest that allergens might also bind IgE in a superantigen-like fashion outside the classic antigen-binding site. OBJECTIVE: We sought to evaluate the contribution of the classic CDR-H3-centric antigen-binding site to the development of an allergic phenotype. METHODS: Using a murine model of experimental asthma, we characterized a gene-targeted mouse strain expressing an altered range of CDR-H3s (DeltaD-iD mice) in response to the hydrophobic allergen ovalbumin (OVA). Mutant and wild-type (wt) mice were sensitized intraperitoneally with OVA; non-sensitized mice served as controls. RESULTS: We found the composition of the classic CDR-H3-centric antigen-binding site to be critical for the development of characteristic aspects of allergic asthma. (i) Compared with wt animals, DeltaD-iD mice showed a significantly less pronounced OVA-induced rise in allergen-specific IgE levels and hence in total serum IgE levels. (ii) In addition, DeltaD-iD mice demonstrated a significant reduction in eosinophilic airway inflammation, as well as in interleukin-4 (IL-4), IL-5 and IL-13 levels in BAL fluids. CONCLUSION: Allergic sensitization and airway inflammation depend on the composition of the predominant CDR-H3 repertoire, suggesting that the classic CDR-H3-centric antigen-binding site plays a crucial role in creating the immunological interface between allergen and IgE. Our results further emphasize a central role of IgE, not only in mediating but also in regulating the allergic immune response.
Subject(s)
Asthma/immunology , Complementarity Determining Regions/immunology , Immunoglobulin E/immunology , Immunoglobulin Heavy Chains/immunology , Inflammation/immunology , Mast Cells/immunology , Allergens/immunology , Animals , Asthma/metabolism , Bronchoalveolar Lavage Fluid/immunology , Complementarity Determining Regions/blood , Complementarity Determining Regions/genetics , Cytokines/analysis , Cytokines/immunology , Disease Models, Animal , Eosinophils/immunology , Eosinophils/metabolism , Immunoglobulin E/blood , Immunoglobulin E/genetics , Immunoglobulin G/blood , Immunoglobulin Heavy Chains/blood , Immunoglobulin Heavy Chains/genetics , Inflammation/metabolism , Lung/immunology , Lung/pathology , Mast Cells/metabolism , Mice , Mice, Mutant Strains , Ovalbumin/immunologyABSTRACT
Different classification systems for therapeutic agents exist. The most commonly used one is the ATC Code (ATC: Anatomy, Therapeutic properties, Chemical, pharmacological properties). Here, an alternative classification system (TCAT: Target-Chemistry-Anatomy-Therapy) is proposed which refers to the molecular mechanism of action or rather, target. The main subgroups of targets are: enzymes; substrates, metabolies, proteins; receptors; ion channels; transporter molecules and systems; nucleic acids, ribosomes; physicochemical mechanisms; antigen-antibody reactions; unknown targets. This target-oriented approach may be particularly useful in teaching advanced medicinal chemistry.
