Interruption of CD28-mediated costimulation during allergen challenge protects mice from allergic airway disease Tea Gogishvili, Dr rer nat, Fred Lühder,

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Interruption of CD28-mediated costimulation during allergen challenge protects mice from allergic airway disease Tea Gogishvili, Dr rer nat, Fred Lühder, Dr rer nat, Frank Kirstein, PhD, Natalie E. Nieuwenhuizen, PhD, Sandra Goebbels, Dr rer nat, Sandra Beer-Hammer, Dr rer nat, Klaus Pfeffer, MD, Sebastian Reuter, Dr rer nat, Christian Taube, MD, Frank Brombacher, PhD, Thomas Hünig, Dr rer nat Journal of Allergy and Clinical Immunology Volume 130, Issue 6, Pages 1394-1403.e4 (December 2012) DOI: 10.1016/j.jaci.2012.08.049 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Induced CD28 deletion before allergen challenge prevents the development of airway pathology. A, Induction of OVA-specific airway inflammation and CD28 deletion. B, CD28 deletion before challenge inhibits the recruitment of eosinophils to the airways. C, Hematoxylin and eosin–stained lung tissues (magnification ×200). D, Invasive measurement of airway resistance. Data are shown as means ± SEMs (n = 5) from one of 3 experiments. Eos, Eosinophils; i.n., intranasal; Lymph, lymphocytes; Macr, macrophages; Neutr, neutrophils; TM, tamoxifen. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Treatment with anti-CD28 impairs lung histopathology and improves airway resistance. Representative hematoxylin and eosin staining of lung tissues. Data are shown from one of 3 independent experiments. A, Magnification ×200 and ×400. B, Invasive measurement of airway resistance for the anti-CD28 therapeutically treated group (setting B) performed with increasing doses of methacholine. *P < .05. Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 CD28 blockade reduces inflammatory cell infiltration and cytokine production in the airways. Cellular composition of BAL fluid: A, prophylactic, setting A; B, therapeutic, setting B. Cytokine levels in BAL fluids: C, prophylactic, setting A; D, therapeutic, setting B. Data are presented as means ± SEMs from one of 3 independent experiments (n = 5). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Anti-CD28 therapy improves the balance of infiltrating Treg cells/effector T cells at the site of inflammation. Cells from spleens (Sp), MLNs, and BAL fluid were analyzed by using flow cytometry for expression of CD4 and forkhead box protein 3 (Foxp3). Means ± SEMs are shown (n = 5). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Anti-CD28 therapy (setting 2) changes the profile of the allergen-specific cytokine response. Single-cell suspensions from spleens (Sp) and MLNs of therapeutically treated mice were cultured for 48 hours in the presence of anti-CD3 or with OVA. Means ± SEMs of cell-culture triplicates are shown from one of 3 independent experiments. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Transient blockade (therapeutic, setting C) of CD28 reduces inflammatory cell infiltration and increases the frequency of forkhead box protein 3 (Foxp3)–positive Treg cells in the airways. A, Cells in BAL fluid. B, Frequency and absolute numbers of Foxp3+ CD4 T cells. C, Cytokines in in vitro–stimulated cell cultures. Values represent means ± SEMs (n = 5). Eos, Eosinophils; lymph, lymphocytes; Macr, macrophages; neutr, neutrophils; Sp, spleen. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 CD28 blockade reduces airway resistance and inflammatory cell infiltration in the airways. A, Airway resistance to methacholine of HDM- or PBS-sensitized/challenged and anti-CD28–treated mice. B, Cells in BAL fluid. BAL fluid eosinophils were analyzed by using fluorescence-activated cell sorting. C, Hematoxilin and eosin–stained lung tissues. D, Effector memory CD4 T cells in the lung. Values represent means ± SEMs from one of 3 experiment (n = 6). *P < .05; **P < .01; and ***P < .001. Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Generation of CD28flox mice. A, A LoxP site was cloned into a genomic CD28 clone from a 129/SvJ mouse upstream of exon 2 together with a neo/TK cassette flanked by 2 LoxP sites in the intron between exon 3 and 4, resulting in the targeting vector. This was electroporated into 129 embryonic stem cells, and after identification of positive clones, the neo/TK cassette was removed by means of transient expression of cre, resulting in the CD28flox allele. Embryonic stem cells harboring this modification were injected into C57Bl/6 blastocysts, resulting in CD28flox mice that were backcrossed 9 times to the C57Bl/6 background. After crossing with appropriate cre-expressing mice, both exon 2 and exon 3 of CD28 will be deleted (CD28Δ). The position of the primers for the screening strategy of the LoxP1 and LoxP2 sites are indicated by bars. Restriction sites: E, EcoRV; K, KpnI; N, NotI; Neo, neomycin; S, SalI; Sp, SpeI; TK, thymidine kinase. B, PCR screening strategy. The LoxP site upstream from exon 2 produced a 718-bp PCR product (lane 3), which was absent in the wild-type allele (lane 2). The LoxP site in the intron between exon 3 and exon 4 was detected by using PCR, resulting in 2 bands of equal intensity of 406 bp (floxed allele) and 297 bp (wild-type allele, lane 5); only the latter was present in wild-type embryonic stem cells (lane 4). Lane 1, Marker with the indicated molecular weights (in base pairs). C, Loss of cell-surface expression of CD28 in CD28−/flox Cre+/− mice after induced gene deletion. Spleen, MLN, and BAL fluid cells were stained for CD4 and CD28. Expression of CD28 is shown for CD4+ T cells. The solid histogram indicates the isotype control. Experiments were done 3 times with at least 5 animals per group. Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Inducible gene deletion in CD28−/flox mice reduces TH2-associated cytokine secretion without changing the OVA-specific response. A, Cytokines in BAL fluid. B, Frequency and absolute cell number of Treg cells. Means ± SEMs from one of 3 experiments are shown (n = 5). Sp, Spleen. *P < .05. Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Blockade of CD28 during sensitization prevents production of OVA-specific IgE but has little effect in therapeutic setting B. A, Antigen-specific IgE levels in sera of mice treated with anti-CD28 during sensitization. B, Levels of OVA-specific IgE in therapeutically treated mice. OVA-specific IgE levels were measured by means of ELISA 1 week after intranasal challenge. Means ± SEMs of one of 3 independent experiments are shown (n = 6-7). Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Anti-CD28 treatment reduces CD4 T-cell infiltration in lung tissues and numbers of cytokine-producing CD4 T cells. Total CD3+CD4+ T-cell numbers and cytokine-producing CD4+ T-cell numbers were identified by means of fluorescence-activated cell sorting in the lung tissue. Values represent means ± SEMs from one of 3 experiments (n = 4). *P < .05; **P < .01; and ***P < .001. Journal of Allergy and Clinical Immunology 2012 130, 1394-1403.e4DOI: (10.1016/j.jaci.2012.08.049) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions