Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Hu.4-1BB-Fc fusion protein inhibits allergic inflammation and airway hyperresponsiveness in a murine model of asthma

  • Kim, Byoung-Ju (Department of Pediatrics, Inje University College of Medicine) ;
  • Kwon, Ji-Won (Department of Pediatrics, Seoul National University College of Medicine) ;
  • Seo, Ju-Hee (Department of Pediatrics, University of Ulsan College of Medicine) ;
  • Choi, Won-Ah (Asan Institute for Life Science) ;
  • Kim, Young-Jun (Asan Institute for Life Science) ;
  • Kang, Mi-Jin (Asan Institute for Life Science) ;
  • Yu, Jin-Ho (Department of Pediatrics, University of Ulsan College of Medicine) ;
  • Hong, Soo-Jong (Department of Pediatrics, University of Ulsan College of Medicine)
  • Received : 2010.07.28
  • Accepted : 2011.07.20
  • Published : 2011.09.15
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Abstract

Purpose: 4-1BB (CD 137) is a costimulatory molecule expressed on activated T-cells. Repression by 4-1BB is thought to attenuate Th2-mediated allergic reactions. The aim of this study was to investigate the effect of 4-1BB on allergic airway inflammation in a murine asthma model. Methods: BALB/c mice were sensitized to and challenged with ovalbumin (OVA). Hu.4-1BB-Fc was administered 1 day before the first OVA sensitization or 1 day after the second OVA sensitization. Following antigen challenge, airway responsiveness to methacholine was assessed and bronchoalveolar lavage (BAL) fluid was analyzed. Total immunoglobulin (Ig) E, OVA-specific IgE, $IgG_1$, and $IgG_{2a}$ levels in sera were measured by enzyme-linked immunosorbent assay. Lung pathology was also evaluated. Results: In mice treated with Hu.4-1BB-Fc before the first OVA sensitization, there was a marked decrease in airway hyperresponsiveness, total cell count, and eosinophil count in the BAL fluid. In addition, Hu.4-1BB-Fc treatment decreased serum OVA-specific $IgG_1$ levels and increased serum $IgG_{2a}$ level significantly compared with the corresponding levels in mice sensitized to and challenged with OVA. Hu.4-1BB-Fc-treated mice also showed suppressed peribronchial and perivascular inflammatory cell infiltration. In contrast, treatment with Hu.4-1BB-Fc 1 day after sensitization had no effect on airway hyperresponsiveness and showed less suppression of inflammation in lung tissue. Conclusion: Administration of Hu.4-1BB-Fc can attenuate airway inflammation and hyperreactivity in a mouse model of allergic airway inflammation. In addition, administration before sensitization may be more effective. These findings suggest that 4-1BB may be a useful therapeutic molecule against asthma.

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References

  1. Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol 2003;3:609-20. https://doi.org/10.1038/nri1148
  2. Watts TH, DeBenedette MA. T cell co-stimulatory molecules other than CD28. Curr Opin Immunol 1999;11:286-93. https://doi.org/10.1016/S0952-7915(99)80046-6
  3. DeBenedette MA, Chu NR, Pollok KE, Hurtado J, Wade WF, Kwon BS, et al. Role of 4-1BB ligand in costimulation of T lymphocyte growth and its upregulation on M12 B lymphomas by cAMP. J Exp Med 1995; 181:985-92. https://doi.org/10.1084/jem.181.3.985
  4. Hurtado JC, Kim YJ, Kwon BS. Signals through 4-1BB are costimulatory to previously activated splenic T cells and inhibit activation-induced cell death. J Immunol 1997;158:2600-9.
  5. Mittler RS, Bailey TS, Klussman K, Trailsmith MD, Hoffmann MK. Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy. J Exp Med 1999;190:1535-40. https://doi.org/10.1084/jem.190.10.1535
  6. Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellstrom KE, et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med 1997;3:682-5. https://doi.org/10.1038/nm0697-682
  7. Halstead ES, Mueller YM, Altman JD, Katsikis PD. In vivo stimulation of CD137 broadens primary antiviral CD8+ T cell responses. Nat Immunol 2002;3:536-41 https://doi.org/10.1038/ni798
  8. Sun Y, Chen HM, Subudhi SK, Chen J, Koka R, Chen L, et al. Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat Med 2002;8:1405-13. https://doi.org/10.1038/nm1202-796
  9. Seo SK, Choi JH, Kim YH, Kang WJ, Park HY, Suh JH, et al. 4-1BB mediated immunotherapy of rheumatoid arthritis. Nat Med 2004;10: 1088-94. https://doi.org/10.1038/nm1107
  10. Lee SW, Croft M. 4-1BB as a therapeutic target for human disease. In: Grewal IS, editor. Therapeutic targets of the TNF superfamily. New York: Springer, 2010:121-9.
  11. Lombardi V, Singh AK, Akbari O. The role of costimulatory molecules in allergic disease and asthma. Int Arch Allergy Immunol 2010;151:179-89. https://doi.org/10.1159/000242355
  12. Fukushima A, Yamaguchi T, Ishida W, Fukata K, Mittler RS, Yagita H, et al. Engagement of 4-1BB inhibits the development of experimental allergic conjunctivitis in mice. J Immunol 2005;175:4897-903.
  13. Sun Y, Blink SE, Liu W, Lee Y, Chen B, Solway J, et al. Inhibition of Th2-mediated allergic airway inflammatory disease by CD137 costimulation. J Immunol 2006;177:814-21.
  14. Polte T, Foell J, Werner C, Hoymann HG, Braun A, Burdach S, et al. CD137-mediated immunotherapy for allergic asthma. J Clin Invest 2006; 116:1025-36. https://doi.org/10.1172/JCI23792
  15. Jang SO, Kim BJ, Yu J, Song YH, Kang MJ, Choi WA, et al. Human cytotoxic T lymphocyte-associated antigen 4-immunoglobulin fusion protein inhibits airway inflammation and hyperresponsiveness in a murine model of asthma. Korean J Asthma Allergy Clin Immunol 2008; 28:205-13.
  16. Curtis JL, Byrd PK, Warnock ML, Kaltreider HB. Requirement of CD4-positive T cells for cellular recruitment to the lungs of mice in response to a particulate intratracheal antigen. J Clin Invest 1991;88:1244-54. https://doi.org/10.1172/JCI115428
  17. Umetsu DT, McIntire JJ, Akbari O, Macaubas C, DeKruyff RH. Asthma: an epidemic of dysregulated immunity. Nat Immunol 2002;3:715-20. https://doi.org/10.1038/ni0802-715
  18. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985-97. https://doi.org/10.1056/NEJMoa051378
  19. Cho YS, Kwon B, Lee TH, Kim TB, Moon KA, La S, et al. 4-1 BB stimulation inhibits allergen-specific immunoglobulin E production and airway hyper-reactivity but partially suppresses bronchial eosinophilic inflammation in a mouse asthma model. Clin Exp Allergy 2006;36:377-85. https://doi.org/10.1111/j.1365-2222.2006.02445.x
  20. Kroczek R, Hamelmann E. T-cell costimulatory molecules: optimal targets for the treatment of allergic airway disease with monoclonal antibodies. J Allergy Clin Immunol 2005;116:906-9. https://doi.org/10.1016/j.jaci.2005.07.005
  21. Sumi T, Ishida W, Mittler RS, Yagita H, Taguchi O, Fukushima A. Regulatory T cells participate in 4-1BB-mediated suppression of experimental allergic conjunctivitis. Int Arch Allergy Immunol 2009;148: 305-10. https://doi.org/10.1159/000170384

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