Targeted suppression of Dpt-specific B cells in humanized Rag2- γc- mouse model of HDM allergy.
Nikola Ralchev RalchevNikola KerekovNikolina Mihaylova MihaylovaMariann KremlitzkaDiana HristovaJulian DzhorevAnna ErdeiAndrey Ivanov TchorbanovPublished in: Scandinavian journal of immunology (2022)
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.
Keyphrases
- cell therapy
- mouse model
- endothelial cells
- induced apoptosis
- atopic dermatitis
- end stage renal disease
- chronic kidney disease
- monoclonal antibody
- ejection fraction
- type diabetes
- stem cells
- acute lymphoblastic leukemia
- cell cycle arrest
- adipose tissue
- signaling pathway
- induced pluripotent stem cells
- metabolic syndrome
- combination therapy
- high fat diet induced
- prognostic factors
- heavy metals
- transcription factor
- cancer therapy
- endoplasmic reticulum stress
- climate change
- tyrosine kinase
- patient reported outcomes
- mesenchymal stem cells
- health risk
- human health
- protein protein
- pluripotent stem cells