eNews October 19, 2010

Some day everyone might be able to eat peanuts

One in 25 Americans is allergic to some kind of food. Food allergies are even more common in children, with one in 17 children under 3 years old having a food allergy. In fact, the incidence of peanut allergies in children has tripled since 1997 (Kids With Food Allergies: a World of Support). The consequences of eating a food that you are allergic to can be quite serious, even fatal. For years, scientists have been trying to better understand and treat food allergies. Among those scientists are Dr. Shau-Ku Huang and his colleagues at the Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland. Dr. Huang's team in 2010 reported that pre-sensitizing mice to a sugar-modified antigen can lessen their allergic reactions to the antigen (Zhou et al. 2010).

Sweetened antigen lessens allergic reaction

C3H/HeJ mice (C3H, 000659) are very allergic to bovine serum albumin. To determine if pre-sensitizing these mice to modified BSA might condition them to react more mildly to the primary antigen, Dr. Huang's team pre-sensitized one group of C3H mice to BSA and another group to sweetened BSA (Man51-BSA – BSA coupled to mannoside – a glycoside of the sugar mannose). The team then challenged both groups with BSA and found that whereas the BSA-sensitized mice develop a strong allergic reaction to BSA, the Man51-BSA-sensitized mice become only mildly allergic to it. They exhibit significantly lower levels of plasma histamine, lower vascular permeability and lower serum levels of BSA-specific IgE, IgG1 and IgG2a antibodies than do BSA-sensitized mice. Additionally, mice that receive adoptive transfers of splenocytes from Man51-BSA-sensitized mice exhibit significantly lower concentrations of plasma histamine than mice that receive adoptive transfers of splenocytes from BSA-sensitized mice.

Man51-BSA binds to SIGNR1-expressing dendritic cells

C3H/HeJ mice sensitized to Man51-BSA become only mildly allergic to BSA.

By profiling the expression patterns of dendritic cells in the intestines of the Man51-BSA-sensitized C3H mice, Huang's team found that Man51-BSA selectively binds to a "CD11c+CD11b+" subset of lamina propria dendritic cells (LPDCs), and that this cell subset expresses the SIGNR1 receptor. An analysis of intestinal dendritic cells from IL10GFP knockin "tiger" mice – from strain B6.129S6-Il10tm1Flv/J (008379) – confirmed this: GFP expression in the CD11c+CD11b+ subset of these mice is significantly higher if they are sensitized to Man51-BSA. The team established that the SIGNR1 receptor preferentially binds to Man51-BSA instead of to other similar or closely related molecules.

Man51-BSA affects T cell differentiation

Dr. Huang's team found that culturing LPDCs with Man51-BSA affects T cell differentiation. Specifically, significantly more IL10- and IFNG-producing T cells are generated if LPDCs are cultured with Man51-BSA than if cultured with BSA. A similar pattern occurs in vivo. Significantly more IL10- and IFNG-producing CD4+ type 1 regulatory (Tr1)-like T cells are produced in the spleens of Man51-BSA-treated mice than in the spleens of BSA-treated mice – and mice that receive adoptive transfers of these CD4+ Tr1-like T cells react relatively mildly to BSA.

Man51-BSA sensitization is ineffective in SIGNR1- and IL10-deficient mice

The reporter strain B6.129S6-Il10tm1Flv/J can be used to detect and monitor cells committed to produce IL10.

Earlier in their study, Dr. Huang's team found that Man51-BSA induces the expression of IL10 in a CD11c+CD11b+ subset of LPDCs. In subsequent experiments, they demonstrated that both SIGNR1 and IL10 are necessary for Man51-BSA to induce BSA tolerance. If SIGNR1-deficient C57BL/6 mice are sensitized with Man51-BSA, neither IL10 nor IFNG production is induced. Additionally, these SIGNR1-deficient mice are significantly more allergic to Man51-BSA than are wild-type B6J (000664) mice, even though B6J mice typically have poorer IgE and TH2 responses and are less allergic to BSA than are C3H mice. Additionally, BSA tolerance is not induced in either C3H mice whose IL10R receptors are blocked or in B6J mice that receive adoptive transfers of splenic CD4+ T cells from Man51-BSA—treated IL10-deficient B6.129P2-Il10tm1Cgn/J (002251) mice.

In summary, Dr. Huang's team found that Man51-BSA, a sugar-modified BSA antigen, can lessen the allergic reaction to BSA in mice. Man51-BSA binds to a unique SIGNR1-expressing subset (CD11c+CD11b+) of lamina propria dendritic cells (LPDCs) in the small intestine, inducing splenic T cells to differentiate, in an IL10-dependent manner, into CD4+, Tr1-like cells that express IL10 and IFNG. The findings suggest that pre-sensitizing people to similarly modified food allergens could substantially reduce their allergic reactions to certain foods.

Reference

Zhou Y, Kawasaki H, Hsu S-C, Lee RT, Yao X, Plunkett B, Fu J, Yang K, Lee YC, Huang S-K. 2010. Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1. Nat Med Sep 12.