An in vivo model of allergic inflammation: pulmonary human cell infiltrate in allergen‐challenged allergic Hu‐SCID mice

Abstract

CB.17 severe combined immunodeficient (SCID) mice were used to establish a model of allergic pulmonary inflammation. SCID mice were intraperitoneally reconstituted with 10(7) peripheral blood mononuclear cells (PBMC) from patients sensitive to Dermatophagoides pteronyssinus (Dpt) and 2 weeks later were exposed to Dpt aerosols. After Dpt nebulization, SCID mice engrafted with PBMC from Dpt-sensitive patients developed a specific human IgE response as well as an intense pulmonary infiltrate of human cells. In contrast, SCID mice reconstituted with PBMC from patients allergic to grass pollen or from non-allergic donors failed to produce IgE or to exhibit a similar inflammatory response. The level of the IgE production was dependent on the IgE level of the allergic donor. In the lungs of the same allergic SCID mice, 2 months after Dpt inhalation, the cell infiltrate contained CD45+, CD45RO+, CD20+ and HLA-DR+ human cells. They were located in perivascular and peribronchial areas and disseminated in the mouse lung parenchyma. Moreover, mRNA IL-5+ cells and eosinophils were found in peribronchial infiltrates. The observations indicate that humanized allergic SCID mice may develop, after nebulization with the relevant allergen, immune reactions similar to those observed in man and suggest that SCID mice may represent a useful model to analyze the regulatory mechanisms of IgE-associated allergic diseases.

Human Dendritic Cells in the Severe Combined Immunodeficiency Mouse Model: Their Potentiating Role in the Allergic Reaction

“…As previously described in other works (Duez et al, 1996;, the number of human CD45 ϩ cells in the lungs of SCID mice reconstituted with PBMC from allergic patients was largely higher (90 Ϯ 7 cells/mm 2 ) than the number of human cells detected in the lungs of SCID mice reconstituted with PBMC from healthy donors (6 Ϯ 1 cells/mm 2 ). Interestingly, when the mice were reconstituted with PBMC from asthmatic allergic patients, the number of CD1a ϩ cells was 8-fold higher than in nonallergic SCID mice ( p ϭ 0.02).…”

“…In a first step, the presence of dendritic cells in the lungs of SCID mice previously reconstituted with PBMC of atopic patients or healthy donors was investigated. When exposed to allergen aerosols, humanized SCID mice produced IgE and developed a pulmonary inflammatory infiltrate consisting of human CD45ϩ cells, primarily CD4ϩ T cells (Duez et al, 1996). The present results show that human dendritic cells are detectable in lungs of hu-SCID mice developing a lung infiltrate.…”

“…Sections were incubated for 1 hour with the following primary antibodies specific for human markers: CD1a (Dako), CD83 (Immunotech), HLAclass II (Dako), CD68 (Dako), CD45 (Becton Dickinson), DC-LAMP (specific for mature DCs), and DCGM4 (specific for immature DCs, kindly provided by Serge Lebecque; Schering Plough, Dardilly, France) or an isotype-matched mouse IgG (Dako) as a negative control. After saturation with 10% normal human serum diluted in TBS, sections were stained using an APAAP technique (Dako) previously described (REF) (Duez et al, 1996), repeated once to increase the sensitivity of the reaction. All slides were lightly counterstained with hematoxylin (Sigma, St Louis, Missouri).…”

“…The three characteristic features of allergic asthma are present in the humanized severe combined immunodeficiency (SCID) mice model. After intraperitoneal reconstitution with mononuclear cells and exposure to Dermatophagoides pteronyssinus (Dpt) aerosols, SCID mice produced human IgE antibodies (Pestel et al, 1994) and developed a pulmonary inflammatory reaction mainly characterized by an infiltrate of activated CD4 ϩ CD45RO ϩ HLA-DR ϩ T cells (Duez et al, 1996;. Moreover, allergic hu-SCID mice exhibited an airway hyper-responsiveness to carbachol (Duez et al, 2000).…”

New Biotechnologycal Approaches for Immunotherapy of Autoimmune Diseases

“…Der p 1, a 222-amino acid glycoprotein, is one of the major allergenic molecules of Dpt. Different approaches have been used for mapping B-and t-cell epitopes of Der p 1. using conventional predictive methods and a tridimensional model of Der p 1, four peptides were selected as potential B cell epitopes and were shown to exhibit ige-dependent biological activities (22,58). One of them, peptide p52-71 (NQSLDLAEQELVDCASQHGC), is used as a model epitope in the engineered chimeric molecule.…”