Allergy prevention starts before conception: Maternofetal transfer of tolerance protects against the development of asthma Tobias Polte, PhD, Christian.

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Allergy prevention starts before conception: Maternofetal transfer of tolerance protects against the development of asthma Tobias Polte, PhD, Christian Hennig, MD, Gesine Hansen, MD Journal of Allergy and Clinical Immunology Volume 122, Issue 5, Pages 1022-1030.e5 (November 2008) DOI: 10.1016/j.jaci.2008.09.014 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Tolerization and immunization protocol. For induction of oral tolerance, BALB/c, C57Bl/6J, or FcRn-deficient mice, which cannot transport immunoglobulin through the placenta, received OVA orally on days −6 and −3 before mating. Some neonates were given to naive wet nurses immediately after birth. The offspring at the age of 6 to 10 weeks or at the age of 7 to 8 months were immunized intraperitoneally with OVA on days 0 and 14, followed by OVA administered intranasally on days 14 to 16 and 21 to 23. One day after the last intranasal challenge (day 24), AHR was measured. Mice were killed on day 25. i.n., Intranasal; i.p., intraperitoneal. Journal of Allergy and Clinical Immunology 2008 122, 1022-1030.e5DOI: (10.1016/j.jaci.2008.09.014) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Tolerization of BALB/c mice before conception prevents the development of an asthma-like phenotype in the offspring. Lung tissues from offspring of tolerized mothers revealed reduced inflammation (hematoxylin and eosin stain, original magnification ×200) and mucus hypersecretion (periodic acid–Schiff stain, original magnification ×200) in the OVA-immunized group compared with that seen in the OVA-immunized offspring from naive mothers (A). This was confirmed by an objective, investigator-independent, computer-based quantification of lung inflammation (B) and mucus hypersecretion (C). Cell numbers in the BAL fluid (D), AHR (E), OVA-specific IgE levels (F), and TH2 cytokine production (G) of splenocytes from the OVA-immunized offspring of tolerized mothers were significantly reduced compared with those seen in the OVA-immunized offspring of naive mothers. Data are expressed as means ± SEMs (n ≥ 9 animals per group). ∗P < .05, 1-way ANOVA and the Bonferroni multiple comparisons test. Penh, Enhanced pause. Journal of Allergy and Clinical Immunology 2008 122, 1022-1030.e5DOI: (10.1016/j.jaci.2008.09.014) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Transfer of tolerance from mothers to offspring is long-lasting and not crucially dependent on breast-feeding. BALB/c mice were tolerized to OVA before mating. Some neonates were given to naive wet nurses immediately after birth. The offspring were immunized with OVA at the age of 7 to 8 months (see Fig 1). Inflammation (A) and mucus production (B) quantified by using a computer-based image-analyzing program, total cell number in BAL fluid (C), AHR (D), OVA-specific IgE serum levels (E), and TH2 cytokine production (F) in spleen cell cultures were significantly reduced, even when the offspring was immunized as late as 7 to 8 months after birth. Data are expressed as means ± SEMs (n ≥ 9 animals per group). ∗P < .05, 1-way ANOVA and the Bonferroni multiple comparisons test. n.s., Not significant; Penh, enhanced pause. Journal of Allergy and Clinical Immunology 2008 122, 1022-1030.e5DOI: (10.1016/j.jaci.2008.09.014) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Maternofetal transfer of tolerance is mediated by antigen-specific IgG antibodies. In wild-type animals OVA-specific IgG1 levels were increased in the sera of pregnant mice and the fetus, the amniotic fluid, and the milk when mice were tolerized before conception (A). The decrease of antigen-specific antibodies after birth was time dependent (B). FcRn−/− mice were tolerized before mating, and some neonates were weaned by naive wet nurses immediately after birth. OVA-specific IgG1 levels were increased in the sera of pregnant mice, in the milk, and in the sera of the wet-nursed neonates when mice were tolerized before conception but not in the sera of the fetus and of the cross-fostered neonate (C). Lung inflammation (D), total cell numbers in the BAL fluid (E), AHR (F), and OVA-specific IgE serum levels (G) were significantly reduced in the offspring of tolerized 6.129X1-Fcgrttm1Dcr mothers but not in their offspring nurtured by wet nurses. For Fig 4, A through C, data are expressed as means ± SEMs (n ≥ 5 animals per group). ∗P < .05. For Fig 4, D through G, data are expressed as means ± SEMs (n ≥ 9 animals per group). ∗P < .05, 1-way ANOVA and the Bonferroni multiple comparisons test. CON, Control; Penh, enhanced pause. Journal of Allergy and Clinical Immunology 2008 122, 1022-1030.e5DOI: (10.1016/j.jaci.2008.09.014) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Maternofetal transfer of tolerance depends on IFN-γ. In vivo blocking of IFN-γ significantly increased the degree of inflammation in the lung (A), the number of eosinophils in the BAL fluid (B), the methacholine-induced AHR (C), the OVA-specific IgE levels (D), and TH2 cytokine production (E) from spleen cell cultures, although it had no effect on the asthma phenotype of the OVA-immunized control group that was born of naive mothers. The control mAb had no effect on any of the tested groups (data not shown). Data are expressed as means ± SEMs (n ≥ 9 animals per group). ∗P < .05, 1-way ANOVA and the Bonferroni multiple comparisons test. Penh, Enhanced pause. Journal of Allergy and Clinical Immunology 2008 122, 1022-1030.e5DOI: (10.1016/j.jaci.2008.09.014) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Tolerization of BALB/c mice prevents the development of an asthma-like phenotype in response to the same antigen. BALB/c mice were tolerized to OVA orally (100 mg) on days −6 and −3 and immunized and challenged with OVA, as described in the Methods section. Lung inflammation (A), mucus production (B), cell numbers in the BAL fluid (C), AHR (D), OVA-specific IgE serum levels (E), and TH2 cytokine production (F) of splenocytes from the OVA-immunized tolerized mice were significantly reduced compared with values seen in the OVA-immunized control mice. Data are expressed as means ± SEMs (n ≥ 9 animals per group). ∗P < .05, 1-way ANOVA and the Bonferroni multiple comparisons test. TOL, Tolerized; Penh, enhanced pause. Journal of Allergy and Clinical Immunology 2008 122, 1022-1030.e5DOI: (10.1016/j.jaci.2008.09.014) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Transfer of tolerance is allergen specific Transfer of tolerance is allergen specific. BALB/c mice were tolerized to OVA before conception, and the offspring were immunized with BLG at the age of 6 to 10 weeks. AHR (A), total cell numbers in the BAL fluid (B), and BLG-specific IgE levels (C) were not affected in the offspring of OVA-tolerized mothers. Data are expressed as means ± SEMs (n ≥ 9 animals per group). ∗P < .05, 1-way ANOVA and the Bonferroni multiple comparisons test. Journal of Allergy and Clinical Immunology 2008 122, 1022-1030.e5DOI: (10.1016/j.jaci.2008.09.014) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Offspring of naive BALB/c mice foster nursed by mice tolerized before conception are prevented from the development of an asthma-like phenotype. Neonates from naive mice were given to tolerized wet nurses immediately after birth. The offspring were immunized with OVA at the age of 6 to 10 weeks. Inflammation (A), total cell numbers in the BAL fluid (B), AHR (C), and OVA-specific IgE levels in the serum (D) were significantly reduced. Data are expressed as means ± SEMs (n ≥ 7 animals per group). ∗P < .05, 1-way ANOVA and the Bonferroni multiple comparisons test. Penh, Enhanced pause. Journal of Allergy and Clinical Immunology 2008 122, 1022-1030.e5DOI: (10.1016/j.jaci.2008.09.014) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Offspring of tolerized FcRn−/− mice foster nursed by mice tolerized before conception are prevented from development of an asthma-like phenotype. Total cell numbers in the BAL fluid (A), AHR (B), and OVA-specific IgE serum levels (C) were significantly reduced. Data are expressed as means ± SEMs (n ≥ 7 animals per group). ∗P < .05, 1-way ANOVA and the Bonferroni multiple comparisons test. Journal of Allergy and Clinical Immunology 2008 122, 1022-1030.e5DOI: (10.1016/j.jaci.2008.09.014) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Antigen stimulation of splenocytes induces IFN-γ–producing memory T cells in naive mice of tolerized mothers. Splenocytes were isolated from the offspring of BALB/c mice (4 months old) that had been tolerized to OVA before conception. OVA stimulation induced IFN-γ production in spleen cells, although the offspring had not directly been in contact with OVA before (A). Phenotype of OVA-specific IFN-γ–producing splenocytes from offspring of tolerized mothers (B). Expression of lineage markers (DN, CD4 and CD8 double-negative T cells). Exemplary picture of an IFN-γ–producing CD8 T cell: the cell shows an activated, blastic phenotype (C). n ≥ 3 animals per group. ∗P < .05. Fig E5, A, Data are expressed as means ± SEMs from 3 independent experiments. Fig E5, B and C, Representative results from 1 of 3 experiments are shown. NK, Natural killer. Journal of Allergy and Clinical Immunology 2008 122, 1022-1030.e5DOI: (10.1016/j.jaci.2008.09.014) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions