Modeling Principle

The Sheep Allergic Rhinitis Model is a SCI gold-standard large-animal pathological model of allergic rhinitis established by intraperitoneal basic sensitization combined with aluminum hydroxide adjuvant plus local nasal challenge with ovalbumin (OVA). It accurately recapitulates full typical pathological and behavioral manifestations of clinical allergic rhinitis, including nasal mucosal congestion and edema, massive eosinophil infiltration, abundant secretion of Th2 inflammatory factors, Th1/Th2 immune imbalance, nasal hyperresponsiveness, sneezing, watery rhinorrhea and nasal pruritus, and compensates for experimental defects of rodent animals with tremendous differences from humans in nasal cavity volume, layered nasal mucosal structure, distribution of respiratory immune cells, nasal ventilation mechanics and allergen immune response pathways.

The nasal anatomical structure, epithelial/lamina propria layers of nasal mucosa, distribution of nasal mucosal microvessels, mucosal-associated lymphoid tissue (MALT) of respiratory tract, Th1/Th2 immune regulatory axis and eosinophil chemotaxis pathway of adult sheep are highly homologous to human upper respiratory tract. Intraperitoneal injection of OVA combined with adjuvant induces systemic sensitization, stimulating the body to produce OVA-specific IgE which binds to nasal mucosal mast cells. Subsequent daily intranasal instillation of OVA solution for local challenge triggers mast cell degranulation to release immediate inflammatory mediators such as histamine and leukotrienes, inducing instant nasal mucosal edema, vasodilation and excessive gland secretion. Repeated continuous challenge activates dendritic cells to massively secrete Th2-dominant cytokines including IL-4, IL-5 and IL-13 while suppressing Th1 factors such as IFN-γ, forming stable Th1/Th2 imbalance. Sustained infiltration of massive eosinophils, mast cells and lymphocytes in nasal lamina propria leads to typical allergic symptoms including frequent sneezing, watery nasal discharge and repeated nose rubbing. This model fully recapitulates the classic pathogenic cascade of human allergic rhinitis: systemic sensitization-local nasal challenge-mast cell degranulation-Th2 inflammatory storm-chronic inflammatory remodeling of nasal mucosa.

Sheep possess sufficient nasal cavity volume to realize precise quantitative intranasal administration, dynamic collection of nasal secretions and real-time observation of mucosal morphology via nasal endoscopy. The temporal sequence of allergic inflammation is stable with minimal individual dispersion and no spontaneous respiratory allergic diseases. It can clearly distinguish three-stage phenotypes including latent period of basic sensitization, peak stage of acute allergic inflammation and stable stage of chronic nasal mucosal remodeling, serving as a standardized large-animal gold-standard model for translational research on allergic rhinitis pathogenesis, intranasal anti-allergic drugs, nasal mucosal repair preparations and desensitization therapy regimens.

Modeling Success Criteria

Macroscopic Nasal Behavior and Endoscopic Mucosal Phenotype

The nasal cavity of sheep in blank control group was dry without frequent sneezing, nose rubbing and watery rhinorrhea within 30 min. The nasal mucosa was light pink, thin and flat under nasal endoscope without congestion, edema or secretion accumulation. At Day 42 terminal point of modeling, the model group presented frequent continuous sneezing, repeated forceful nose rubbing and massive watery nasal discharge within 30 min after each OVA challenge. Diffuse dark red congestion, obvious edema, narrowed nasal cavity and massive transparent secretions attached could be observed under nasal endoscope. The persistent allergic phenotype was typical with extremely significant inter-group difference, confirming preliminary successful construction of allergic rhinitis model.

Quantitative Biochemical Gold-Standard Indexes of Serum and Nasal Secretions

Serum total IgE and OVA-specific sIgE in model group were extremely significantly higher than blank control group; massive release of histamine and leukotrienes in nasal secretions and nasal mucosa; Th2-type factors IL-4, IL-5 and IL-13 were sharply upregulated while Th1 factor IFN-γ decreased remarkably with inverted Th1/Th2 ratio; high expression of eosinophil chemokines in nasal mucosa, fully matching the core biochemical diagnostic characteristics of clinical persistent allergic rhinitis: elevated IgE, release of mast cell degranulation mediators, Th2-dominant immune imbalance and massive eosinophil recruitment.

Nasal Mucosa Histopathological Characteristics

Combined HE, toluidine blue and eosin staining of nasal mucosal tissues showed characteristic temporal pathological changes of allergic rhinitis:

1. Late sensitization stage at Day 21 after modeling: mild nasal mucosal congestion, a small amount of activated mast cells without obvious eosinophil infiltration;
2. Inflammatory peak stage at Day 35 after modeling: thickened nasal mucosal epithelium, dilated edematous lamina propria, diffuse infiltration of massive eosinophils, mast cells and lymphocytes, hypertrophic hyperplastic glands;
3. Terminal remodeling stage at Day 42 after modeling: thickened nasal mucosal epithelial layer, basement membrane fibrosis, sustained massive inflammatory cell infiltration in lamina propria, excessive secretory hyperplasia of glands and dilated congested blood vessels, which perfectly recapitulates graded pathological characteristics of acute inflammation and chronic mucosal remodeling of human persistent allergic rhinitis.

Core Th1/Th2 Immunity and Mast Cell Activation Pathway Indexes

The TLR4/NF-κB inflammatory pathway of nasal mucosa in model group was persistently activated to drive dendritic cells to secrete massive Th2 cytokines; the mast cell FcεRI pathway was overactivated with degranulation releasing histamine and leukotrienes; Th1 differentiation signals were inhibited with differentiation bias toward Th2, and eosinophil chemotaxis pathway remained continuously open. It accurately conforms to the complete immune pathogenic mechanism induced by OVA sensitization and challenge: systemic IgE production-nasal mast cell sensitization and degranulation-Th2 dominant inflammatory imbalance-chronic inflammatory remodeling of nasal mucosa, serving as core academic criterion for confirming successful modeling.

Model Advantages

This model is a well-recognized exclusive large-animal gold-standard model of OVA-induced persistent allergic rhinitis in otolaryngology allergy SCI field. 42-day compound modeling combined with systemic sensitization and repeated nasal challenge stably constructs IgE-mediated allergic rhinitis with Th2 dominant imbalance and chronic nasal mucosal inflammatory remodeling highly homologous to humans. Sheep possess large nasal cavity volume, layered nasal mucosal structure, respiratory immune cell distribution and allergic attack behavioral manifestations highly close to human beings, with uniform inflammatory progression sequence, extremely low intra-group data dispersion and far higher reproducibility than small animals such as mice and guinea pigs. The modeling mechanism accurately simulates human persistent allergic rhinitis induced by inhaled allergens such as pollen and dust mites, without non-specific inflammatory interference caused by simple local stimulation and hormone intervention. Behavioral scoring, dynamic nasal endoscopic observation, non-invasive nasal secretion sampling and multi-dimensional quantitative detection of immune inflammation can be carried out synchronously. It is suitable for preclinical large-animal efficacy and safety evaluation of nasal spray anti-allergic preparations, oral antihistamines, leukotriene receptor antagonists, nasal mucosal repair gels and specific desensitization vaccines. Sufficient samples can be obtained with extremely high clinical transformation credibility and high recognition in high-score SCI journals of otolaryngology, allergy and respiratory medicine, suitable for National Natural Science Foundation, master/doctor project opening, graduation thesis of otolaryngology/allergology and translational medical research on mucosal immunity of allergic rhinitis.

Research Applications

The Sheep Allergic Rhinitis Model is corely applied to basic research on OVA-induced systemic IgE synthesis, nasal mast cell FcεRI activation and degranulation, TLR4/NF-κB-mediated Th2 inflammatory storm, Th1/Th2 immune imbalance and chronic remodeling of nasal mucosal epithelial fibrosis. It is specially used for screening and evaluating nasal spray small-molecule anti-allergic drugs, oral anti-allergic preparations, natural plant anti-inflammatory extracts, nasal mucosal repair biological gels and specific desensitization vaccines with effects of inhibiting IgE production, blocking mast cell degranulation, downregulating Th2 cytokines, restoring Th1/Th2 balance, alleviating nasal mucosal edema and eosinophil infiltration and delaying basement membrane fibrosis. It is widely adopted for excavation of mucosal immune pathogenic targets of allergic rhinitis, elucidation of upper respiratory tract Th1/Th2 regulatory network, and large-animal preclinical in-vivo verification of rhinitis prevention drugs and nasal preparations, serving as a scarce and essential standardized large-animal gold-standard model in the fields of otolaryngology allergy, respiratory mucosal immunity and allergy pharmacology.

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