Characterization of the Immunogenicity and Allergenicity of Two Cow's Milk Hydrolysates – A Study in Brown Norway Rats

Bøgh, Katrine Lindholm; Barkholt, Vibeke; Madsen, Charlotte Bernhard

doi:10.1111/sji.12271

Cited by 28 publications

(17 citation statements)

References 34 publications

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“…Such models would be particularly useful for the preclinical screening of candidates for new IF products before trials are conducted on humans, which is required by recent EU regulation of IF products to allow labelling of health claims. We previously assessed the allergenicity of hydrolysed IFs in high IgE-responder BN rats, and our findings reflected those of other studies in animals and humans [16, 18]. Here, we developed 2 new models using this allergy-prone rat strain for the assessment of the primary preventive and desensitising capacity of whey-based hydrolysed IF.…”

Section: Discussionsupporting

confidence: 48%

Preclinical Brown Norway Rat Models for the Assessment of Infant Formulas in the Prevention and Treatment of Cow’s Milk Allergy

Jensen

Larsen

Madsen

et al. 2019

Int Arch Allergy Immunol

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Background: Infant formulas (IFs) based on hydrolysed cow’s milk proteins are central in the management of cow’s milk allergy (CMA) in infants and small children. New IF compositions with improved prevention and treatment properties are needed, along with appropriate preclinical animal models, to evaluate these properties before introduction into humans. Objectives: We aimed to develop preclinical models for the assessment of the primary preventive and desensitising capacity of cow’s milk IF in allergy-prone, high-IgE responder Brown Norway rats. Method: Preventive capacity was assessed in cow’s milk-naïve rats given a 2- or 4-week regimen of whey-based extensively hydrolysed IF (eHF), partially hydrolysed IF (pHF), or intact β-lactoglobulin (BLG) ad libitum in drinking bottles, followed by intraperitoneal (i.p.) immunisation with BLG. Desensitising capacity was assessed in orally BLG-sensitised rats after a 3- or 6-week regimen of eHF, pHF, or intact BLG administration in drinking bottles, followed by i.p. challenge with BLG. Primary preventive and desensitising capacity were analysed by serum BLG-specific IgG1 and IgE. Results: The preventive regimens did not induce detectable BLG-specific IgG1 or IgE in cow’s milk-naïve rats. A preventive regimen consisting of pHF or BLG, but not eHF, induced complete tolerance to BLG, as demonstrated by the absence of BLG-specific IgE following i.p. immunisation. Desensitising regimens had a limited effect on BLG-specific IgG1 or IgE when comparing sensitised rats before and after treatment. Challenge with BLG (i.p.) increased BLG-specific IgE in all treatment regimens except for in the BLG group, suggesting a limited desensitising capacity of IF based on hydrolysates and a need for the presence of intact allergen for desensitisation. Conclusions: The presented models highlight that different mechanisms are at play in the induction of de novo tolerance to cow’s milk proteins and the desensitisation of CMA. Different IF products may be needed for the primary prevention and treatment of CMA.

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Section: Discussionsupporting

confidence: 48%

Preclinical Brown Norway Rat Models for the Assessment of Infant Formulas in the Prevention and Treatment of Cow’s Milk Allergy

Jensen

Larsen

Madsen

et al. 2019

Int Arch Allergy Immunol

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“…28 For evaluation of the antigen-antibody binding strength, avidity IgG1 ELISA was performed as described. 28 For evaluation of the specificity of the antigen-antibody binding, inhibitory IgG1 ELISA was performed as previously described 29 with the exception that sera were pre-incubated with WPI and HT-WPI inhibitor solutions.…”

Section: Analysis Of Product-specific Igg1 By Various Elisasmentioning

confidence: 99%

Cow’s milk allergy prevention and treatment by heat‐treated whey—A study in Brown Norway rats

Graversen

Ballegaard

Kræmer

et al. 2020

Clin Experimental Allergy

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Background: Food processing, including heat-treatment, can affect protein structure and stability, and consequently affect protein immunogenicity and allergenicity. A few studies have shown that structural changes induced by heat-treatment impact the intestinal protein uptake and suggest this as a contributing factor for altered allergenicity.Objective: To investigate the impact of heat-treatment of a whey-based protein product on allergenicity and tolerogenicity as well as on intestinal uptake in various animal models.Methods: Immunogenicity and sensitizing capacity of the heat-treated whey product were compared to that of the unmodified product by intraperitoneal and oral exposure studies, while tolerogenic properties were assessed by oral primary prevention and desensitization studies in high-IgE responder Brown Norway rats. Results:Heat-treatment of whey induced partial protein denaturation and aggregation, which reduced the intraperitoneal sensitizing capacity but not immunogenicity. In contrast, heat-treatment did not influence the oral sensitizing capacity, but the heat-treated whey showed a significantly reduced eliciting capacity compared to unmodified whey upon oral challenge. Heat-treatment did not reduce the tolerogenic properties of whey, as both products were equally good at preventing sensitization in naïve rats as well as desensitizing already sensitized rats. Results from inhibitory ELISA and immunoblots with sera from sensitized rats demonstrated that heat-treatment caused an altered protein and epitope reactivity. Protein uptake studies showed that heat-treatment changed the route of uptake with less whey being absorbed through the epithelium but more into the Peyer's patches. Conclusion and Clinical Relevance:These results support the notion that the physicochemical features of proteins affect their route of uptake and that the route of uptake may affect the protein allergenicity. Furthermore, the study highlights the potential for heat-treatment in the production of efficient and safe cow's milk proteinbased products for prevention and treatment of cow's milk allergy. K E Y W O R D S allergens and epitopes, animal models, food allergy, food processing, IgE, intestinal uptake, paediatrics | 709 GRAVERSEN Et Al. How to cite this article: Graversen KB, Ballegaard A-SR, Kraemer LH, et al. Cow's milk allergy prevention and treatment by heat-treated whey-A study in Brown Norway rats. Clin Exp Allergy. 2020;50:708-721. https://doi.

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“…The mechanisms behind the adjuvant effect of aluminum hydroxide are still not fully understood [ 62 ], but stimulation of DC antigen presentation [ 63 ] and a IL-4-driven Th2 response have been described [ 64 ]. Additionally, changes in specific antibody responses to aluminum hydroxide-adsorbed antigens have been observed [ 62 , 65 , 66 ] and is probably due to the modulation of antibody responses related to structural changes of the antigens [ 67 ].…”

Section: Adjuvantsmentioning

confidence: 99%

Current challenges facing the assessment of the allergenic capacity of food allergens in animal models

Bøgh

Bilsen²,

Głogowski

et al. 2016

Clin Transl Allergy

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Food allergy is a major health problem of increasing concern. The insufficiency of protein sources for human nutrition in a world with a growing population is also a significant problem. The introduction of new protein sources into the diet, such as newly developed innovative foods or foods produced using new technologies and production processes, insects, algae, duckweed, or agricultural products from third countries, creates the opportunity for development of new food allergies, and this in turn has driven the need to develop test methods capable of characterizing the allergenic potential of novel food proteins. There is no doubt that robust and reliable animal models for the identification and characterization of food allergens would be valuable tools for safety assessment. However, although various animal models have been proposed for this purpose, to date, none have been formally validated as predictive and none are currently suitable to test the allergenic potential of new foods. Here, the design of various animal models are reviewed, including among others considerations of species and strain, diet, route of administration, dose and formulation of the test protein, relevant controls and endpoints measured.

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Characterization of the Immunogenicity and Allergenicity of Two Cow's Milk Hydrolysates – A Study in Brown Norway Rats

Cited by 28 publications

References 34 publications

Preclinical Brown Norway Rat Models for the Assessment of Infant Formulas in the Prevention and Treatment of Cow’s Milk Allergy

Preclinical Brown Norway Rat Models for the Assessment of Infant Formulas in the Prevention and Treatment of Cow’s Milk Allergy

Cow’s milk allergy prevention and treatment by heat‐treated whey—A study in Brown Norway rats

Current challenges facing the assessment of the allergenic capacity of food allergens in animal models

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