nitrophenols and aluminum-sulfate

Asthmatic inflammation is dominated by accumulation of either eosinophils, neutrophils, or both in the airways. Disposal of these inflammatory cells is the key to disease control. Eosinophilic airway inflammation is responsive to corticosteroid treatment, whereas neutrophilic inflammation is resistant and increases the burden of global health care. Corticosteroid-resistant neutrophilic asthma remains mechanistically poorly understood and requires novel effective therapeutic strategies.. We sought to explore the underlying mechanisms of airway inflammation persistence, as well as corticosteroid resistance, and to investigate a new strategy of effective treatment against corticosteroid-insensitive neutrophilic asthma.. Mouse models of either eosinophil-dominated or neutrophil-dominated airway inflammation were used in this study to test corticosteroid sensitivity in vivo and in vitro. We also used vav-Bcl-2 transgenic mice to confirm the importance of granulocytes apoptosis in the clearance of airway inflammation. Finally, the Bcl-2 inhibitors ABT-737 or ABT-199 were tested for their therapeutic effects against eosinophilic or neutrophilic airway inflammation and airway hyperresponsiveness.. Overexpression of Bcl-2 protein was found to be responsible for persistence of granulocytes in bronchoalveolar lavage fluid after allergic challenge. This was important because allergen-induced airway inflammation aggravated and persisted in vav-Bcl-2 transgenic mice, in which nucleated hematopoietic cells were overexpressed with Bcl-2 and resistant to apoptosis. The Bcl-2 inhibitors ABT-737 or ABT-199 play efficient roles in alleviation of either eosinophilic or corticosteroid-resistant neutrophilic airway inflammation by inducing apoptosis of immune cells, such as eosinophils, neutrophils, T. Apoptosis of inflammatory cells is essential for clearance of allergen-induced airway inflammation. The Bcl-2 inhibitors ABT-737 or ABT-199 might be promising drugs for the treatment of airway inflammation, especially for corticosteroid-insensitive neutrophilic airway inflammation.

Topics: Adrenal Cortex Hormones; Allergens; Alum Compounds; Animals; Anti-Inflammatory Agents; Apoptosis; Asthma; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bronchoalveolar Lavage Fluid; Dexamethasone; Drug Resistance; Eosinophils; Freund's Adjuvant; Humans; Lung; Male; Mice, Inbred C57BL; Mice, Transgenic; Neutrophils; Nitrophenols; Ovalbumin; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Exposure of naïve B cells to the cytokine interleukin-4 (IL-4) and/or antigen leads to a state of "priming," in which subsequent aggregation of major histocompatibility complex class II molecules induces the mobilization of calcium ions and cell proliferation. However, it is not clear how critical this priming is for immune responses or how it is normally induced in vivo. Injection of mice with the commonly used adjuvant alum led to priming of splenic B cells and to the accumulation in the spleen of a previously unknown population of IL-4-producing, Gr1+ cells. These cells and IL-4 were both required for in vivo priming and expansion of antigen-specific B cells, as well as for optimal production of antibody. These studies reveal a key role for a previously unknown accessory myeloid cell population in the generation of humoral immune responses.

Topics: Adjuvants, Immunologic; Adoptive Transfer; Alum Compounds; Animals; B-Lymphocytes; Calcium; Cell Separation; Cells, Cultured; Coculture Techniques; Eosinophils; Freund's Adjuvant; Granulocyte-Macrophage Colony-Stimulating Factor; Histocompatibility Antigens Class II; Immunization; Interleukin-4; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Myeloid Cells; Nitrophenols; Serum Albumin, Bovine; Signal Transduction; Spleen

Cr2-/- mice have an impairment in humoral immunity, as shown by the decrease in the Ab titers against T cell-dependent Ags and abnormalities in germinal center formation. Germinal centers are present, but they are decreased in size and number, indicating problems in their development. In this study, we investigated whether this abnormality in germinal center development is associated with problems in the establishment of optimal affinity maturation and the generation of memory B cells, processes closely related to the germinal center reaction. We immunized the Cr2-/- animals with different Ags with or without adjuvants. We showed that, when immunized without adjuvants, complement receptors are absolutely required for optimal affinity maturation. Although limited affinity maturation is elicited in the Cr2-/- Ab response, it is decreased as compared with normal animals. Memory B cell generation is also impaired. In the presence of adjuvants, germinal center development in the Cr2-/- mice is still abnormal, as demonstrated by their decreased size and number. Surprisingly, adjuvants establish optimal affinity maturation and partially restore the amount of Ab produced during the primary response and memory B cell generation. However, adjuvants cannot improve the ability of follicular dendritic cells to retain Ags in the form of immune complexes. These observations indicate that immunization with inflammatory Ags offset some of the immunological abnormalities found in the Cr2-/- mice and show that optimal affinity maturation in the Cr2-/- mice can be achieved in the absence of normal germinal centers.

Topics: Adjuvants, Immunologic; Alum Compounds; Animals; Antibody Affinity; Antigens; B-Lymphocyte Subsets; Base Sequence; Cell Differentiation; Dendritic Cells, Follicular; Germinal Center; Haptens; Hemocyanins; Immunoglobulin G; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Immunologic Deficiency Syndromes; Immunologic Memory; Injections, Intraperitoneal; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Mutation; Nitrophenols; Phenylacetates; Receptors, Complement 3d; Spleen