Similar articles

Abstract: Objective: Airway inflammation and airway hyper-responsiveness (AHR) are principle pathological manifestations of asthma. cluster of differentiation 69 (CD69) is a well-known co-stimulatory factor associated with the activation, proliferation as well as apoptosis of immune cells. This study aims to examine the effect of anti-CD69 monoclonal antibody (mAb) on the pathophysiology of a mouse model of asthma. Methods: A murine model of ovalbumin (OVA)-induced allergic airway inflammation was used in this study. Briefly, mice were injected with 20 μg chicken OVA intraperitoneally on Days 0 and 14, followed by aerosol provocation with 1% (0.01 g/ml) OVA on Days 24, 25, and 26. Anti-CD69 mAb or isotype IgG was injected intraperitoneally after OVA challenge; dexamethasone (DXM) was administrated either before or after OVA challenge. AHR, mucus production, and eosinophil infiltration in the peribronchial area were examined. The levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) in bronchoalveolar lavage fluid (BALF) were also assayed as indices of airway inflammation on Day 28 following OVA injection. Results: Pretreatment with DXM together with anti-CD69 mAb treatment after OVA provocation completely inhibited AHR, eosinophil infiltration and mucus overproduction, and significantly reduced BALF IL-5. However, treatment with DXM alone after OVA challenge only partially inhibited AHR, eosinophil infiltration and mucus overproduction, and did not diminish BALF IL-5. Treatment with either DXM or anti-CD69 mAb did not alter the concentration of BALF GM-CSF. Conclusions: Anti-CD69 mAb treatment inhibits established airway inflammation as effectively as DXM pretreatment. This study provides a potential alternative therapeutic opportunity for the clinical management of asthma and its exacerbation.

抗CD69单克隆抗体对哮喘小鼠的气道炎症抑制作用研究

[1]Al-Rabia, M.W., Blaylock, M.G., Sexton, D.W., et al., 2004. Membrane receptor-mediated apoptosis and caspase activation in the differentiated EoL-1 eosinophilic cell line. J. Leukoc. Biol., 75(6):1045-1055.

[2]Alari-Pahissa, E., Notario, L., Lorente, E., et al., 2012. CD69 does not affect the extent of T cell priming. PLoS ONE, 7(10):e48593.

[3]Antoniu, S.A., 2009. Mepolizumab for difficult-to-control asthma with persistent sputum eosinophilia. Expert Opin. Investig. Drugs, 18(6):869-871.

[4]Asquith, K.L., Ramshaw, H.S., Hansbro, P.M., et al., 2008. The IL-3/IL-5/GM-CSF common receptor plays a pivotal role in the regulation of Th2 immunity and allergic airway inflammation. J. Immunol., 180(2):1199-1206.

[5]Atzeni, F., del Papa, N., Sarzi-Puttini, P., et al., 2004. CD69 expression on neutrophils from patients with rheumatoid arthritis. Clin. Exp. Rheumatol., 22(3):331-334.

[6]Bankovich, A.J., Shiow, L.R., Cyster, J.G., 2010. CD69 suppresses sphingosine 1-phosophate receptor-1 (S1P1) function through interaction with membrane helix 4. J. Biol. Chem., 285(29):22328-22337.

[7]Birrell, M.A., Battram, C.H., Woodman, P., et al., 2003. Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways. Respir. Res., 4(1):3.

[8]Borchers, M.T., Crosby, J., Farmer, S., et al., 2001. Blockade of CD49d inhibits allergic airway pathologies independent of effects on leukocyte recruitment. Am. J. Physiol. Lung Cell Mol. Physiol., 280(4):L813-L821.

[9]Busse, W.W., Lemanske, R.F.J., 2001. Asthma. N. Engl. J. Med., 344(5):350-362.

[10]Busse, W.W., Katial, R., Gossage, D., et al., 2010. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor α antibody, in a phase I study of subjects with mild asthma. J. Allergy Clin. Iimmunol., 125(6):1237-1244.e2.

[11]Castro, M., Mathur, S., Hargreave, F., et al., 2011. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med., 184(10):1125-1132.

[12]Cebrian, M., Yague, E., Rincon, M., et al., 1988. Triggering of T cell proliferation through AIM, an activation inducer molecule expressed on activated human lymphocytes. J. Exp. Med., 168(5):1621-1637.

[13]Corren, J., Busse, W., Meltzer, E.O., et al., 2010. A randomized, controlled, phase 2 study of AMG 317, an IL-4Rα antagonist, in patients with asthma. Am. J. Respir. Crit. Care Med., 181(8):788-796.

[14]Cruz-Adalia, A., Jiménez-Borreguero, L., Ramírez-Huesca, M., et al., 2010. CD69 limits the severity of cardiomyopathy after autoimmune myocarditis. Circulation, 122(14):1396-1404.

[15]Dallaire, M.J., Ferland, C., Page, N., et al., 2003. Endothelial cells modulate eosinophil surface markers and mediator release. Eur. Respir. J., 21(6):918-924.

[16]Epardaud, M., Elpek, K.G., Rubinstein, M.P., et al., 2008. Interleukin-15/interleukin-15Rα complexes promote destruction of established tumors by reviving tumor-resident CD8⁺ T cells. Cancer Res., 68(8):2972-2983.

[17]Esplugues, E., Sancho, D., Vega-Ramos, J., et al., 2003. Enhanced antitumor immunity in mice deficient in CD69. J. Exp. Med., 197(9):1093-1106.

[18]Gauvreau, G.M., Wood, L.J., Sehmi, R., et al., 2000. The effects of inhaled budesonide on circulating eosinophil progenitors and their expression of cytokines after allergen challenge in subjects with atopic asthma. Am. J. Respir. Crit. Care Med., 162(6):2139-2144.

[19]Hamelmann, E., Schwarze, J., Takeda, K., et al., 1997. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med., 156(3):766-775.

[20]Han, S.T., Mosher, D.F., 2014. IL-5 induces suspended eosinophils to undergo unique global reorganization associated with priming. Am. J. Respir. Cell Mol. Biol., 50(3):654-664.

[21]Iwashiro, M., Messer, R.J., Peterson, K.E., et al., 2001. Immunosuppression by CD4⁺ regulatory T cells induced by chronic retroviral infection. PNAS, 98(16):9226-9230.

[22]Justice, J.P., Crosby, J., Borchers, M.T., et al., 2002. CD4⁺ T cell-dependent airway mucus production occurs in response to IL-5 expression in lung. Am. J. Physiol. Lung Cell. Mol. Physiol., 282(5):L1066-L1074.

[23]Lee, J.J., McGarry, M.P., Farmer, S.C., et al., 1997. Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. J. Exp. Med., 185(12):2143-2156.

[24]Letterio, J.J., Roberts, A.B., 1998. Regulation of immune responses by TGF-β. Annu. Rev. Immunol., 16(1):137-161.

[25]Lewkowich, I.P., Rempel, J.D., HayGlass, K.T., 2005. Prevention of allergen-specific, Th2-biased immune responses in vivo: role of increased IL-12 and IL-18 responsiveness. J. Immunol., 175(8):4956-4962.

[26]Luttmann, W., Matthiesen, T., Matthys, H., et al., 1999. Synergistic effects of interleukin-4 or interleukin-13 and tumor necrosis factor-α on eosinophil activation in vitro. Am. J. Respir. Cell Mol. Biol., 20(3):474-480.

[27]Martin, P., Gomez, M., Lamana, A., et al., 2010a. CD69 association with Jak3/Stat5 proteins regulates Th17 cell differentiation. Mol. Cell. Biol., 30(20):4877-4889.

[28]Martin, P., Gomez, M., Lamana, A., et al., 2010b. The leukocyte activation antigen CD69 limits allergic asthma and skin contact hypersensitivity. J. Allergy Clin. Immunol., 126(2):355-365.e3.

[29]Matsumoto, K., Appiah-Pippim, J., Schleimer, R.P., et al., 1998. CD44 and CD69 represent different types of cell-surface activation markers for human eosinophils. Am. J. Respir. Cell Mol. Biol., 18(6):860-866.

[30]McGee, H.S., Agrawal, D.K., 2006. T_H2 cell in the pathogenesis of airway remodeling. Immunol. Res., 35(3):219-232.

[31]Miki-Hosokawa, T., Hasegawa, A., Iwamura, C., et al., 2009. CD69 controls the pathogenesis of allergic airway inflammation. J. Immunol., 183(12):8203-8215.

[32]Mohammadi Nejad, M., Salehi, E., Mesdaghi, M., et al., 2013. Increased expression of CD69 antigen on human peripheral blood natural killer cells in patients with allergic rhinitis. Iran. J. Allergy Asthma Immunol., 12(1):68-74.

[33]Pajusto, M., Ihalainen, N., Pelkonen, J., et al., 2004. Human in vivo-activated CD45R0⁺ CD4⁺ T cells are susceptible to spontaneous apoptosis that can be inhibited by the chemokine CXCL12 and IL-2, -6, -7, and -15. Eur. J. Immunol., 34(10):2771-2780.

[34]Pavord, I.D., Korn, S., Howarth, P., et al., 2012. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet, 380(9842):651-659.

[35]Sancho, D., Gomez, M., Viedma, F., et al., 2003. CD69 downregulates autoimmune reactivity through active transforming growth factor-β production in collagen-induced arthritis. J. Clin. Invest., 112(6):872-882.

[36]Santis, A.G., Campanero, M.R., Alonso, J.L., et al., 1992. Tumor necrosis factor-α production induced in T lymphocytes through the AIM/CD69 activation pathway. Eur. J. Immunol., 22(5):1253-1259.

[37]Sheikh Bahaie, N., Rao, S.P., Massoud, A., et al., 2010. GM-CSF differentially regulates eosinophil and neutrophil adhesive interactions with vascular endothelium in vivo. Iran. J. Allergy Asthma Immunol., 9(4):207-217.

[38]Shen, H.H., Ochkur, S.I., McGarry, M.P., et al., 2003. A causative relationship exists between eosinophils and the development of allergic pulmonary pathologies in the mouse. J. Immunol., 170(6):3296-3305.

[39]Shinoda, K., Tokoyoda, K., Hanazawa, A., et al., 2012. Type II membrane protein CD69 regulates the formation of resting T-helper memory. PNAS, 109(19):7409-7414.

[40]Spencer, L.A., Szela, C.T., Perez, S.A., et al., 2009. Human eosinophils constitutively express multiple Th1, Th2, and immunoregulatory cytokines that are secreted rapidly and differentially. J. Leukoc. Biol., 85(1):117-123.

[41]Su, Y.C., Rolph, M.S., Hansbro, N.G., et al., 2008. Granulocyte-macrophage colony-stimulating factor is required for bronchial eosinophilia in a murine model of allergic airway inflammation. J. Immunol., 180(4):2600-2607.

[42]Takatsu, K., Nakajima, H., 2008. IL-5 and eosinophilia. Curr. Opin. Immunol., 20(3):288-294.

[43]Testi, R., D'Ambrosio, D., de Maria, R., et al., 1994. The CD69 receptor: a multipurpose cell-surface trigger for hematopoietic cells. Immunol. Today, 15(10):479-483.

[44]Tugores, A., Alonso, M.A., Sanchez-Madrid, F., et al., 1992. Human T cell activation through the activation-inducer molecule/CD69 enhances the activity of transcription factor AP-1. J. Immunol., 148(7):2300-2306.

[45]Unutmaz, D., Pileri, P., Abrignani, S., 1994. Antigen-independent activation of naive and memory resting T cells by a cytokine combination. J. Exp. Med., 180(3):1159-1164.

[46]van Rijt, L.S., Prins, J.B., Leenen, P.J., et al., 2002. Allergen-induced accumulation of airway dendritic cells is supported by an increase in CD31^hiLy-6C^neg bone marrow precursors in a mouse model of asthma. Blood, 100(10):3663-3671.

[47]Vance, B.A., Harley, P.H., Backlund, P.S., et al., 2005. Human CD69 associates with an N-terminal fragment of calreticulin at the cell surface. Arch. Biochem. Biophys., 438(1):11-20.

[48]Vega-Ramos, J., Alari-Pahissa, E., Valle, J.D., et al., 2010. CD69 limits early inflammatory diseases associated with immune response to Listeria monocytogenes infection. Immunol. Cell Biol., 88(7):707-715.

[49]Walsh, G.M., Williamson, M.L., Symon, F.A., et al., 1996. Ligation of CD69 induces apoptosis and cell death in human eosinophils cultured with granulocyte-macrophage colony-stimulating factor. Blood, 87(7):2815-2821.

[50]Wang, H.Y., Shen, H.H., Lee, J.J., et al., 2006. CD69 expression on airway eosinophils and airway inflammation in a murine model of asthma. Chin. Med. J. (Engl.), 119(23):1983-1990.

[51]Zhao, Q., Kuang, D.M., Wu, Y., et al., 2012. Activated CD69⁺ T cells foster immune privilege by regulating IDO expression in tumor-associated macrophages. J. Immunol., 188(3):1117-1124.