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Costimulation through B7-2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (TH2) immune response and altered airway responsiveness.

Tsuyuki S, Tsuyuki J, Einsle K, Kopf M, Coyle AJ - J. Exp. Med. (1997)

Bottom Line: The anti-B7-2, but not anti-B7-1, mAb also inhibited antigen-induced airway hyperresponsiveness in vivo.In all of the parameters assessed, the combination of both the anti-B7-1 and anti-B7-2 mAb was no more effective than anti-B7-2 mAb treatment alone.We propose that strategies aimed at inhibition of CD28 interactions with B7-2 molecules may represent a novel therapeutic target for the treatment of lung mucosal allergic inflammation.

View Article: PubMed Central - PubMed

Affiliation: R&D Dept. Kissei Pharmaceutical Co. Ltd., Matsumoto, Japan.

ABSTRACT
The recruitment of eosinophils into the airways after allergen exposure is dependent on interleukin (IL) 5 secreted from antigen-specific CD4+ T cells of the T helper cell (Th) 2 subset. However, while it is established that costimulation through CD28 is required for TCR-mediated activation and IL-2 production, the importance of this mechanism for the induction of a Th2 immune response is less clear. In the present study, we administered the fusion protein CTLA-4 immunoglobulin (Ig) into the lungs before allergen provocation to determine whether CD28/CTLA-4 ligands are required for allergen-induced eosinophil accumulation and the production of Th2 cytokines. Administration of CTLA-4 Ig inhibited the recruitment of eosinophils into the lungs by 75% and suppressed IgE in the bronchoalveolar lavage fluid. CTLA-4 Ig also inhibited the production of IL-4, IL-5, and IL-10 by 70-80% and enhanced interferon-gamma production from CD3-T cell receptor-activated lung Thy1.2+ cells. Allergen exposure upregulated expression of B7-2, but not B7-1, on B cells from the lung within 24 h. Moreover, airway administration of an anti-B7-2 monoclonal antibody (mAb) inhibited eosinophil infiltration, IgE production, and Th2 cytokine secretion comparable in magnitude to that observed with CTLA-4 Ig. Treatment with an anti-B7-1 mAb had a small, but significant effect on eosinophil accumulation, although was less effective in inhibiting Th2 cytokine production. The anti-B7-2, but not anti-B7-1, mAb also inhibited antigen-induced airway hyperresponsiveness in vivo. In all of the parameters assessed, the combination of both the anti-B7-1 and anti-B7-2 mAb was no more effective than anti-B7-2 mAb treatment alone. We propose that strategies aimed at inhibition of CD28 interactions with B7-2 molecules may represent a novel therapeutic target for the treatment of lung mucosal allergic inflammation.

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Inhibition of airway hyperresponsiveness to  methacholine by an anti-B7-2  mAb. (A) Mice were immunized  and exposed to either an aerosol  of PBS or OVA for 5 consecutive days. (B) Effect of anti-B7-1  and/or B7-1 mAb on antigeninduced AHR. Control mice  were treated with rat IgG. Results are expressed as the mean ±  SEM of the Penh before (open  bar) and after (  filled bar). MCh  provocation for n = 4–6 animals.  Statistical significance (*) was determined by a Student's t test and  a value of P <0.05 was considered to be significant.
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Figure 8: Inhibition of airway hyperresponsiveness to methacholine by an anti-B7-2 mAb. (A) Mice were immunized and exposed to either an aerosol of PBS or OVA for 5 consecutive days. (B) Effect of anti-B7-1 and/or B7-1 mAb on antigeninduced AHR. Control mice were treated with rat IgG. Results are expressed as the mean ± SEM of the Penh before (open bar) and after (  filled bar). MCh provocation for n = 4–6 animals. Statistical significance (*) was determined by a Student's t test and a value of P <0.05 was considered to be significant.

Mentions: We next investigated whether B7-1 and/or B7-2 contribute to the development of airway hyperresponsiveness (AHR) to methacholine (MCh). Allergen provocation of immunized mice treated with control rat Ig resulted in the development of AHS (baseline Penh, 0.37 ± 0.04; after MCh, 2.8 ± 0.27, n = 5), as compared to immunized mice treated with control rat Ig and exposed to PBS (baseline Penh, 0.39 ± 0.01; after MCh 0.56 ± 0.03, n = 4, P >0.05; Fig. 8 A). There was no change in AHR in PBS-exposed mice that were treated with either B7-1 and/or B7-2 mAb (data not shown). Pretreatment with anti-B7-2 mAb abrogated the development of allergen-induced AHR (baseline Penh, 0.39 ± 0.04; after MCh, 0.90 ± 0.33, P <0.05). In contrast, anti-B7-1 mAb had no significant effect, and the MCh response was comparable to that observed in Ig-treated, antigen-exposed mice. (baseline Penh, 0.35 ± 0.03; after MCh, 3.38 ± 0.85, P = 0.48). Pretreatment with the combination of anti-B7-1 and B7-2 mAbs was no more effective than antiB7-2 mAb treatment alone AHR (baseline Penh, 0.36 ± 0.02; after MCh, 0.70 ± 0.16, P >0.05), compared to anti-B7-2 mAb treatment alone (Fig. 8 B).


Costimulation through B7-2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (TH2) immune response and altered airway responsiveness.

Tsuyuki S, Tsuyuki J, Einsle K, Kopf M, Coyle AJ - J. Exp. Med. (1997)

Inhibition of airway hyperresponsiveness to  methacholine by an anti-B7-2  mAb. (A) Mice were immunized  and exposed to either an aerosol  of PBS or OVA for 5 consecutive days. (B) Effect of anti-B7-1  and/or B7-1 mAb on antigeninduced AHR. Control mice  were treated with rat IgG. Results are expressed as the mean ±  SEM of the Penh before (open  bar) and after (  filled bar). MCh  provocation for n = 4–6 animals.  Statistical significance (*) was determined by a Student's t test and  a value of P <0.05 was considered to be significant.
© Copyright Policy
Related In: Results  -  Collection

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Figure 8: Inhibition of airway hyperresponsiveness to methacholine by an anti-B7-2 mAb. (A) Mice were immunized and exposed to either an aerosol of PBS or OVA for 5 consecutive days. (B) Effect of anti-B7-1 and/or B7-1 mAb on antigeninduced AHR. Control mice were treated with rat IgG. Results are expressed as the mean ± SEM of the Penh before (open bar) and after (  filled bar). MCh provocation for n = 4–6 animals. Statistical significance (*) was determined by a Student's t test and a value of P <0.05 was considered to be significant.
Mentions: We next investigated whether B7-1 and/or B7-2 contribute to the development of airway hyperresponsiveness (AHR) to methacholine (MCh). Allergen provocation of immunized mice treated with control rat Ig resulted in the development of AHS (baseline Penh, 0.37 ± 0.04; after MCh, 2.8 ± 0.27, n = 5), as compared to immunized mice treated with control rat Ig and exposed to PBS (baseline Penh, 0.39 ± 0.01; after MCh 0.56 ± 0.03, n = 4, P >0.05; Fig. 8 A). There was no change in AHR in PBS-exposed mice that were treated with either B7-1 and/or B7-2 mAb (data not shown). Pretreatment with anti-B7-2 mAb abrogated the development of allergen-induced AHR (baseline Penh, 0.39 ± 0.04; after MCh, 0.90 ± 0.33, P <0.05). In contrast, anti-B7-1 mAb had no significant effect, and the MCh response was comparable to that observed in Ig-treated, antigen-exposed mice. (baseline Penh, 0.35 ± 0.03; after MCh, 3.38 ± 0.85, P = 0.48). Pretreatment with the combination of anti-B7-1 and B7-2 mAbs was no more effective than antiB7-2 mAb treatment alone AHR (baseline Penh, 0.36 ± 0.02; after MCh, 0.70 ± 0.16, P >0.05), compared to anti-B7-2 mAb treatment alone (Fig. 8 B).

Bottom Line: The anti-B7-2, but not anti-B7-1, mAb also inhibited antigen-induced airway hyperresponsiveness in vivo.In all of the parameters assessed, the combination of both the anti-B7-1 and anti-B7-2 mAb was no more effective than anti-B7-2 mAb treatment alone.We propose that strategies aimed at inhibition of CD28 interactions with B7-2 molecules may represent a novel therapeutic target for the treatment of lung mucosal allergic inflammation.

View Article: PubMed Central - PubMed

Affiliation: R&D Dept. Kissei Pharmaceutical Co. Ltd., Matsumoto, Japan.

ABSTRACT
The recruitment of eosinophils into the airways after allergen exposure is dependent on interleukin (IL) 5 secreted from antigen-specific CD4+ T cells of the T helper cell (Th) 2 subset. However, while it is established that costimulation through CD28 is required for TCR-mediated activation and IL-2 production, the importance of this mechanism for the induction of a Th2 immune response is less clear. In the present study, we administered the fusion protein CTLA-4 immunoglobulin (Ig) into the lungs before allergen provocation to determine whether CD28/CTLA-4 ligands are required for allergen-induced eosinophil accumulation and the production of Th2 cytokines. Administration of CTLA-4 Ig inhibited the recruitment of eosinophils into the lungs by 75% and suppressed IgE in the bronchoalveolar lavage fluid. CTLA-4 Ig also inhibited the production of IL-4, IL-5, and IL-10 by 70-80% and enhanced interferon-gamma production from CD3-T cell receptor-activated lung Thy1.2+ cells. Allergen exposure upregulated expression of B7-2, but not B7-1, on B cells from the lung within 24 h. Moreover, airway administration of an anti-B7-2 monoclonal antibody (mAb) inhibited eosinophil infiltration, IgE production, and Th2 cytokine secretion comparable in magnitude to that observed with CTLA-4 Ig. Treatment with an anti-B7-1 mAb had a small, but significant effect on eosinophil accumulation, although was less effective in inhibiting Th2 cytokine production. The anti-B7-2, but not anti-B7-1, mAb also inhibited antigen-induced airway hyperresponsiveness in vivo. In all of the parameters assessed, the combination of both the anti-B7-1 and anti-B7-2 mAb was no more effective than anti-B7-2 mAb treatment alone. We propose that strategies aimed at inhibition of CD28 interactions with B7-2 molecules may represent a novel therapeutic target for the treatment of lung mucosal allergic inflammation.

Show MeSH
Related in: MedlinePlus