IngentaConnect Genetic selection for resistance or susceptibility to oral tolera...

Abstract:

Summary Background

Immunological oral tolerance is being studied with great interest due to its therapeutic potential in allergy and autoimmunity processes, although the cellular and molecular mechanisms linking these different phenomena remain elusive. In the present study, two mouse lines with extreme phenotypes for susceptibility [TS Line] or resistance [TR Line] to oral tolerance and their [TS × TR]F₂ segregants were used in order to evaluate the impact of these traits on the atopic potential of the individuals. Objective

Demonstrate whether the tr and ts genes, cumulated during 18 generations of bidirectional genetic selection, influence expression of two important immunobiological traits (IgE and mast cell) critical to allergic response. Methods

Mice with extreme phenotypes for oral tolerance to ovalbumin (OVA), produced by assortative mating (TS and TR Line), and their (TS × TR)F₂ segregating were used. Serum IgE levels assayed by ELISA, and mastocytes counted with toluidine blue staining were evaluated in naïve mice. Anaphylaxis was induced by intravenous injection of OVA, intestinal inflammation by oral administration of OVA 7 days after immunization, and pulmonary inflammation by intranasal and nebulization OVA challenges. Specific IgE was dosed by passive cutaneous anaphylaxis. Results

The naïve TS mice have a 20-fold lower serum IgE level and two- to threefold diminished mast cell numbers in mucosal sites, when compared with TR-mice, which were highly susceptible to allergic inflammation and anaphylactic shock. The associations of oral tolerance, serum IgE levels and mast cell numbers in naïve animals were confirmed analysing the simultaneous presence of these traits in individuals of a [TS × TR]F₂-segregating population. Conclusion

The results suggest that the complex of genes controlling TS and TR phenotypes play a main role in the regulation of the atopic potential of the individual. The studies of these traits in interline F₂ segregants demonstrated a co-segregation of TS and TR phenotypes with IgE responsiveness and mast cell numbers. Thus, the opposite capacity of the genetically modified mice may be involved in co-adaptative mechanisms reflecting a dynamic relation between gene frequencies in a natural population. These correlations give circumstantial evidence to support clinical applications of oral tolerance in allergic and autoimmune diseases.

Keywords: allergic inflammation; co-segregation; genetic selected mice; IgE; mastocytes; oral tolerance; systemic anaphylaxis

Document Type: Research article

DOI: 10.1111/j.1365-2222.2006.02588.x

Affiliations: 1: Departamento de Imunologia, Universidade Federal do Rio de Janeiro, RJ, Brazil, 2: Departamento de Biologia Celular e Genética, Universidade do Estado do Rio de Janeiro, RJ, Brazil, 3: Laboratório de Imunogenética, Instituto Butantan, SP, Brazil and 4: Laboratório de Imunoquímica, Instituto Butantan, SP, Brazil.

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Genetic selection for resistance or susceptibility to oral tolerance imparts correlation to both Immunoglobulin E level and mast cell number phenotypes with a profound impact on the atopic potential of the individual