Targeted suppression of Dpt-specific B cells in humanized Rag2- γc- mouse model of HDM allergy.

Abstract

Der p 1 is one of the major allergenic molecules of Dermatophagoides pteronyssinus, causing house dust mite (HDM) allergy. The pathological B cells produce allergen-specific IgE antibodies that mediate the hypersensitivity reaction, therefore the selective elimination of these B cells is a legitimate therapeutic goal in allergy. Chimeric molecule Dp51-72 able to cross-link B cell inhibitory complement receptor type 1 and BCR on Der p 1-specific B cells was constructed. The signalling capabilities of this molecule have been tested on human B cells. A humanized mouse model of HDM allergy has been used to test the in vivo effects of the chimeric molecule administration. Administering the chimeric molecule to immunodeficient Rag2- γc- mice transferred with PBMCs from allergic patients resulted in reduction of allergen-specific IgE antibodies in the sera, and reduced infiltration of immune cells in lung histology preparations. Reduced numbers of human CD45+ and CD4+ cells in the lungs as well as inhibition of mast cell degranulation were also observed. The treatment with Dp51-72 chimera significantly decreased the local levels of anti-Dpt IgE antibodies in the bronchoalveolar lavage fluid (BALF). The binding of the chimeric molecule to tonsillar B cells triggers the tyrosine phosphorylation of 30-32 kDa protein, which is most likely involved in the inhibitory process. Administration of constructed chimeric molecules to humanized mice with developed inflammation resulted in specific suppression of disease-associated IgE antibody-producing cells and preserved lung histology. This effective approach could be further developed into a therapeutic agent for treatment of patients with HDM allergy.

• Authors: Nikola Ralchev Ralchev, Nikola Kerekov, Nikolina Mihaylova, Mariann Kremlitzka, Diana Hristova, Julian Dzhorev, Anna Erdei, Andrey Ivanov Tchorbanov
• Journal: Scandinavian journal of immunology (Scand J Immunol) Vol. 97 Issue 2 Pg. e13241 (Feb 2023) ISSN: 1365-3083 [Electronic] England
• PMID: 36519562 (Publication Type: Journal Article)
• Copyright: © 2022 The Scandinavian Foundation for Immunology.

Chemical References

• Allergens
• Antigens, Dermatophagoides
• DNA-Binding Proteins
• Immunoglobulin E
• Nuclear Proteins
• RAG2 protein, human
• Rag2 protein, mouse
• Receptors, Antigen, B-Cell

Topics

• Animals
• Humans
• Mice
• Allergens
• Antigens, Dermatophagoides
• Disease Models, Animal
• DNA-Binding Proteins
• Dust Mite Allergy (metabolism)
• Hypersensitivity
• Immunoglobulin E
• Nuclear Proteins
• B-Lymphocytes (drug effects)
• Receptors, Antigen, B-Cell (drug effects)