Interaction between granulocytes and antibodies in the enhancement of lung defenses against Staphylococcus aureus after intranasal immunization of mice with live-attenuated bacteria

An intranasal (i.n.) dosing model was developed in mice as a potential alternative to more difficult, time-consuming, and costly guinea pig intratracheal (GPIT) or mouse intratracheal models for assessment of the respiratory immunogenicity of detergent enzymes. Using a benchmark enzyme, Alcalase (protease subtilisin Carlsberg), studies were conducted to standardize the model in terms of mouse strain, dosing and serum harvest regimen, and the primary immunoglobulin endpoint to use. The primary assay endpoint selected was the enzyme-specific IgG1 titer determined by an Alcalase-specific ELISA. This is not the primary allergenic antibody in mice (IgE is); however, IgG1 is coregulated with IgE via the IL-4/TH2 pathway and may have a role in mediating allergic-type responses. BDF1 mice (C57B1/6 x DBA/2) were selected as representative of high responder strains, with high response associated with the H-2b (C57B1/6) parent. The dosing regimen used for most studies incorporated three i.n. exposures (Days 1, 3, and 10) and bleeding of the animals on Day 15. The animals were anesthetized and then immunized by allowing them to inhale 5-microliters aliquots of dosing solution into each nostril at each immunization. Positioning of the animals with their heads down (vs up) may have allowed more of the dosing solution to remain in the nasal region for a slightly longer period of time, but did not change the eventual GI tract migration and excretion of each dose. The presence of a detergent matrix in the enzyme dosing solution enhanced the IgG1 response. Immunizing with enzyme plus detergent gave highly consistent dose-response curves for Alcalase when evaluated over many studies. An enzyme-specific allergic antibody (IgE) response was weak and inconsistent under the dosing regimen used to generate the IgG1 response, but was stronger with longer-term dosing, consistent with the delay in IgE vs IgG1 responses seen in some other studies. Using IgG1 as a surrogate for allergic sensitization, we have preliminary data showing similar differential potencies between Alcalase and other test enzymes as detected in previous GPIT tests. On the basis of these data, we believe the i.n. immunization/IgG1 response model is a robust technique that may be useful in determining the relative immunogenicities of detergent enzymes and other proteins.

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Specific Antibody Responses to Subtilisin Carlsberg (Alcalase) in Mice: Development of an Intranasal Exposure Model

Robinson

Babcock

Horn

et al. 1996

Fundamental and Applied Toxicology

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Characteristics of the immunological response in the clearance of non‐typeable Haemophilus influenzae from the lung

Kyd

1998

Immunol Cell Biol

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Summary Clearance of non-typeable Haemophilus in¯uenzae (NTHi) from the respiratory tract was investigated, over time, in immune and non-immune rats. A triphasic pattern characterized the clearance of bacteria from the lungs. Mucosal immunization enhanced bacterial clearance from the lungs in each of the three phases compared with clearance from non-immunized animals. Total clearance of bacteria was observed from lung tissue by 12 h in immune animals and 24 h in non-immune animals. Polymorphonuclear leucocytes not only arrived earlier and initially in greater numbers, but disappeared earlier in immune animals (peaking at 8 h postchallenge), compared with non-immune animals (peaking at 12 h post-challenge). Systemically derived and locally produced NTHi-speci®c IgA and IgG correlated with enhanced bacterial clearance during the secondary phase. This model demonstrates that immunized animals up-regulate and resolve in¯ammatory responses to pulmonary infection more rapidly than the non-immunized controls.

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Immunization with Alpha-Toxin Toxoid Protects the Cornea against Tissue Damage during Experimental Staphylococcus aureus Keratitis

et al. 2000

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Interaction between granulocytes and antibodies in the enhancement of lung defenses against Staphylococcus aureus after intranasal immunization of mice with live-attenuated bacteria

Cited by 4 publications

References 20 publications

Specific Antibody Responses to Subtilisin Carlsberg (Alcalase) in Mice: Development of an Intranasal Exposure Model

Specific Antibody Responses to Subtilisin Carlsberg (Alcalase) in Mice: Development of an Intranasal Exposure Model

Characteristics of the immunological response in the clearance of non‐typeable Haemophilus influenzae from the lung

Immunization with Alpha-Toxin Toxoid Protects the Cornea against Tissue Damage during Experimental Staphylococcus aureus Keratitis

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