j res pharm Marmara Pharmaceutical Journal 1309-0801 Marmara University Animal models of asthma Astımda hayvan modelleri Akkoç Tunç 03 06 2014 14 3 104 111 03 06 2014 Copyright © 1985, Marmara Pharmaceutical Journal 1985 Marmara Pharmaceutical Journal

ABSTRACT: Allergic disease such as asthma, rhinitis, and eczema are increasing prevelanceand affect up to 15% of population in Westernized countries. Among them, asthma is achronic inflammatory disease of airways and the underlying physiological and immunologicalprocesses are not fully understood. Mouse models of asthma dupicates many featuresof human asthma, including airway hyperreactivity, andairway inflammation. Therefore, relevantmodels for asthma are important to understand the mechanism of disease and therapeuticalapproach. In this article, basicly various animal models of asthma and some theraputicapproaches are disscussed.KEY WORDS: Asthma,Mouse, Ovalbumin, Regulatory cells

Astım, allerjik rinit, ve ekzema gibi allerjik hastalıların prevelansı özellikle batılı ülkelerde popülasyonun yakla- şık %15’ini etkileyecek şekilde artmaktadır. Bu hastalıklar arasında astım havayollarının inflamatuar bir hastalığıdır ve hastalığın altında yatan fizyolojik ve immunolojik mekanizmalar halen tam olarak açıklanamamıştır. Farelede geliştirilen astım modeli insan astımına çok benzemektedir. Bu yüzden geliştirilen uygun modellerde hem hastalık mekanizması hakkında hem de tedavi yakalşımları hakkında önemli veriler elde edilebilmektedir. Bu derlemede, astım için geliştirilen hayvan modelleri ve tedavi yaklaşımları tartışılmıştır

 - Astım Fare Ovalbumin Regülatör hücreler Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross- sectional surveys. Lancet, 368:733-43, 2006. Janson C, Anto J, Burney P, et al. The European Com- munity Respiratory Health Survey: what are the main results so far? European Community Respiratory Health Survey II. Eur Respir J, 18:598-611, 2001. Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM. Asthma. From bronchoconstriction to airways in- flammation and remodeling. Am J Respir Crit Care Med, 161:1720-45, 2000. Akkoc T, Tolunay S, Barlan I, Basaran M. Airway remod- eling and serum total immunoglobulin E (IgE) levels in a murine model of asthma. J Asthma 2001;38:585-91. Fish JE, Peters SP. Airway remodeling and persistent airway obstruction in asthma. J Allergy Clin Immunol, 104:509-16, 1999. Zosky GR, Sly PD. Animal models of asthma. Clin Exp Allergy 2007;37:973-88. Nials AT, Uddin S. Mouse models of allergic asthma: acute and chronic allergen challenge. Dis Model Mech 1:213-20, 2008. Wagner JG, Harkema JR. Rodent models of allergic rhin- itis: relevance to human pathophysiology. Curr Allergy Asthma Rep 7:134-40, 2007. Dearman RJ, Kimber I. A mouse model for food allergy using intraperitoneal sensitization. Methods 41:91-8, 2007. Jin H, He R, Oyoshi M, Geha RS. Animal models of at- opic dermatitis. J Invest Dermatol 129:31-40, 2009. Niederkorn JY. Immune regulatory mechanisms in al- lergic conjunctivitis: insights from mouse models. Curr Opin Allergy Clin Immunol 8:472-6, 2008. Karol MH. Animal models of occupational asthma. Eur Respir J 7:555-68, 1994. Bice DE, Seagrave J, Green FH. Animal models of asth- ma: potential usefulness for studying health effects of inhaled particles. Inhal Toxicol 12:829-62, 2000. Akdis M, Akdis CA. Therapeutic manipulation of im- mune tolerance in allergic disease. Nat Rev Drug Discov 8:645-60, 2009. Romagnani S. Lymphokine production by human T cells in disease states. Annu Rev Immunol 12:227-57, 1994. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17:138-46, 1996. Corry DB. IL-13 in allergy: home at last. Curr Opin Im- munol 11:610-4, 1999. Schneider T, van Velzen D, Moqbel R, Issekutz AC. Ki- netics and quantitation of eosinophil and neutrophil recruitment to allergic lung inflammation in a brown Norway rat model. Am J Respir Cell Mol Biol 17:702-12, 1997. Bautsch W, Hoymann HG, Zhang Q, et al. Cutting edge: guinea pigs with a natural C3a-receptor defect exhibit decreased bronchoconstriction in allergic airway disease: evidence for an involvement of the C3a anaphylatoxin in the pathogenesis of asthma. J Immunol 165:5401-5, 2000. Shin YS, Takeda K, Gelfand EW. Understanding asthma using animal models. Allergy Asthma Immunol Res 1:10-8, 2009. Noelpp B, Noelpp-Eschenhagen I. [Experimental bron- chial asthma in the guinea pig. IV. Experimental asthma in the guinea pig as an experimental model.]. Int Arch Allergy Appl Immunol 3:207-17, 1952. Ricciardolo FL, Nijkamp F, De Rose V, Folkerts G. The guinea pig as an animal model for asthma. Curr Drug Targets 9:452-65, 2008. Watanabe A, Hayashi H. Allergen-induced biphasic bronchoconstriction in rats. Int Arch Allergy Appl Im- munol 93:26-34, 1990. Bellofiore S, Martin JG. Antigen challenge of sensitized rats increases airway responsiveness to methacholine. J Appl Physiol 65:1642-6, 1988. Ewart SL, Kuperman D, Schadt E, et al. Quantitative trait loci controlling allergen-induced airway hyperre- sponsiveness in inbred mice. Am J Respir Cell Mol Biol 23:537-45, 2000. McIntire JJ, Umetsu SE, Akbari O, et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2:1109-16, 2001. Herz U, Renz H, Wiedermann U. Animal models of type I allergy using recombinant allergens. Methods 32:271- 80, 2004. Kumar RK, Herbert C, Foster PS. The “classical” ovalbu- min challenge model of asthma in mice. Curr Drug Tar- gets 9:485-94, 2008. Fuchs B, Braun A. Improved mouse models of allergy and allergic asthma - chances beyond ovalbumin. Curr Drug Targets 9:495-502, 2008 Conrad ML, Yildirim AO, Sonar SS, et al. Comparison of adjuvant and adjuvant-free murine experimental asthma models. Clin Exp Allergy 39:1246-54, 2009. Johnson JR, Wiley RE, Fattouh R, et al. Continuous ex- posure to house dust mite elicits chronic airway inflam- mation and structural remodeling. Am J Respir Crit Care Med 169:378-85, 2004. Sarpong SB, Zhang LY, Kleeberger SR. A novel mouse model of experimental asthma. Int Arch Allergy Immu- nol 132:346-54, 2003. Blyth DI, Pedrick MS, Savage TJ, Hessel EM, Fattah D. Lung inflammation and epithelial changes in a murine model of atopic asthma. Am J Respir Cell Mol Biol 14:425-38, 1996. Barrett EG, Rudolph K, Bowen LE, Muggenburg BA, Bice DE. Effect of inhaled ultrafine carbon particles on the allergic airway response in ragweed-sensitized dogs. Inhal Toxicol 15:151-65, 2003. Kurup VP, Choi H, Murali PS, Resnick A, Fink JN, Coff- man RL. Role of particulate antigens of Aspergillus in murine eosinophilia. Int Arch Allergy Immunol 112:270- 8, 1997. Chapoval SP, Iijima K, Marietta EV, et al. Allergic in- flammatory response to short ragweed allergenic extract in HLA-DQ transgenic mice lacking CD4 gene. J Immu- nol 168:890-9, 2002. Takeda K, Gelfand EW. Mouse models of allergic dis- eases. Curr Opin Immunol 21:660-5, 2009. Fernandez-Rodriguez S, Ford WR, Broadley KJ, Kidd EJ. Establishing the phenotype in novel acute and chronic murine models of allergic asthma. Int Immunopharma- col 8:756-63 2008. Temelkovski J, Hogan SP, Shepherd DP, Foster PS, Kumar RK. An improved murine model of asthma: se- lective airway inflammation, epithelial lesions and in- creased methacholine responsiveness following chronic exposure to aerosolised allergen. Thorax 53:849-56, 1998. Wegmann M. Animal models of chronic experimental asthma - strategies for the identification of new thera- peutic targets. J Occup Med Toxicol 2008;3 Suppl 1:S4. Kim CH, Ahn JH, Kim SJ, et al. Co-administration of vac- cination with DNA encoding T cell epitope on the Der p and BCG inhibited airway remodeling in a murine mod- el of chronic asthma. J Asthma 43:345-53, 2006. Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunol- ogy 18:723-37, 1970. Groux H, O’Garra A, Bigler M, et al. A CD4+ T-cell sub- set inhibits antigen-specific T-cell responses and pre- vents colitis. Nature 389:737-42, 1997. Akdis CA, Blesken T, Akdis M, Wuthrich B, Blaser K. Role of interleukin 10 in specific immunotherapy. J Clin Invest 102:98-106, 1998. Akdis CA, Blaser K. IL-10-induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy. Faseb J 13:603- 9, 1999. Akdis M, Akdis CA. Mechanisms of allergen-specific im- munotherapy. J Allergy Clin Immunol 119:780-91, 2007. Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG. Differentiation of Tr1 cells by imma- ture dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 105:1162-9, 2005. Barrat FJ, Cua DJ, Boonstra A, et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 195:603-16, 2002. De Smedt T, Van Mechelen M, De Becker G, Urbain J, Leo O, Moser M. Effect of interleukin-10 on dendritic cell maturation and function. Eur J Immunol 27:1229-35, 1997. Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH. Induc- tion of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimula- tion with allogeneic immature human dendritic cells. J Exp Med 192:1213-22, 2000. Akbari O, Freeman GJ, Meyer EH, et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand path- way and inhibit allergen-induced airway hyperreactivity. Nat Med 8:1024-32, 2002. Beier KC, Hutloff A, Dittrich AM, et al. Induction, binding specificity and function of human ICOS. Eur J Immunol 30:3707-17, 2000. Witsch EJ, Peiser M, Hutloff A, et al. ICOS and CD28 re- versely regulate IL-10 on re-activation of human effector T cells with mature dendritic cells. Eur J Immunol 32:2680-6, 2002. Jutel M, Akdis M, Budak F, et al. IL-10 and TGF-beta co- operate in the regulatory T cell response to mucosal al- lergens in normal immunity and specific immunotherapy. Eur J Immunol 33:1205-14, 2003. Nasser SM, Ying S, Meng Q, Kay AB, Ewan PW. Inter- leukin-10 levels increase in cutaneous biopsies of patients undergoing wasp venom immunotherapy. Eur J Immunol 31:3704-13, 2001. Punnonen J, de Waal Malefyt R, van Vlasselaer P, Gauchat JF, de Vries JE. IL-10 and viral IL-10 prevent IL-4-induced IgE synthesis by inhibiting the accessory cell function of monocytes. J Immunol 151:1280-9, 1993. Akdis M, Verhagen J, Taylor A, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 199:1567-75, 2004. Ito T, Wang YH, Duramad O, et al. OX40 ligand shuts down IL-10-producing regulatory T cells. Proc Natl Acad Sci U S A 103:13138-43, 2006. Sakaguchi S. Regulatory T cells: key controllers of immu- nologic self-tolerance. Cell 101:455-8, 2000. Godfrey VL, Wilkinson JE, Russell LB. X-linked lym- phoreticular disease in the scurfy (sf) mutant mouse. Am J Pathol 138:1379-87, 1991. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330-6, 2003. Lyon MF, Peters J, Glenister PH, Ball S, Wright E. The scurfy mouse mutant has previously unrecognized he- matological abnormalities and resembles Wiskott-Aldrich syndrome. Proc Natl Acad Sci U S A 87:2433-7, 1990. Lin W, Truong N, Grossman WJ, et al. Allergic dysregula- tion and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 116:1106-15, 2005. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Im- muno l 4:337-42, 2003. Bennett CL, Christie J, Ramsdell F, et al. The immune dys- regulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20-1, 2001. Chatila TA, Blaeser F, Ho N, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmuni- ty-allergic disregulation syndrome. J Clin Invest 106:R75- 81, 2000. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyen- docrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 39:537-45, 2002. Nieves DS, Phipps RP, Pollock SJ, et al. Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol 140:466-72, 2004. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Sci- ence 299:1057-61, 2003. Yagi H, Nomura T, Nakamura K, et al. Crucial role of FOXP3 in the development and function of hu- man CD25+CD4+ regulatory T cells. Int Immunol 2004;16:1643-56. Gavin M, Rudensky A. Control of immune homeostasis by naturally arising regulatory CD4+ T cells. Curr Opin Immunol 15:690-6, 2003. Sakaguchi S, Powrie F. Emerging challenges in regula- tory T cell function and biology. Science 317:627-9, 2007. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142-51, 2005. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological toler- ance to self and non-self. Nat Immunol 6:345-52, 2005. Ziegler SF. FOXP3: of mice and men. Annu Rev Immu- nol 24:209-26, 2006. Wu Y, Borde M, Heissmeyer V, et al. FOXP3 controls reg- ulatory T cell function through cooperation with NFAT. Cell 126:375-87, 2006. Tuovinen H, Laurinolli TT, Rossi LH, Pekkarinen PT, Mattila I, Arstila TP. Thymic production of human FOXP3(+) regulatory T cells is stable but does not cor- relate with peripheral FOXP3 expression. Immunol Lett 2008. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/ macrophages. Proc Natl Acad Sci U S A 104:19446-51, 2007. Di Ianni M, Del Papa B, De Ioanni M, et al. Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol 36:309-18, 2008. Lewkowich IP, Herman NS, Schleifer KW, et al. CD4+CD25+ T cells protect against experimentally in- duced asthma and alter pulmonary dendritic cell pheno- type and function. J Exp Med 202:1549-61, 2005. Kearley J, Barker JE, Robinson DS, Lloyd CM. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med 202:1539-47, 2005. Leech MD, Benson RA, De Vries A, Fitch PM, Howie SE. Resolution of Der p1-induced allergic airway inflam- mation is dependent on CD4+CD25+Foxp3+ regulatory cells. J Immunol 179:7050-8, 2007. Winkler B, Hufnagl K, Spittler A, et al. The role of Foxp3+ T cells in long-term efficacy of prophylactic and therapeutic mucosal tolerance induction in mice. Allergy 61:173-80, 2006. Doganci A, Sauer K, Karwot R, Finotto S. Pathological role of IL-6 in the experimental allergic bronchial asthma in mice. Clin Rev Allergy Immunol 28:257-70, 2005. Doganci A, Eigenbrod T, Krug N, et al. The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo. J Clin Invest 115:313-25, 2005. Finotto S, Eigenbrod T, Karwot R, et al. Local blockade of IL-6R signaling induces lung CD4+ T cell apoptosis in a murine model of asthma via regulatory T cells. Int Im- munol 19:685-93, 2007. Mascarell L, Van Overtvelt L, Lombardi V, et al. A syn- thetic triacylated pseudo-dipeptide molecule promotes Th1/TReg immune responses and enhances tolerance induction via the sublingual route. Vaccine 26:108-18, 2007. Van Overtvelt L, Lombardi V, Razafindratsita A, et al. IL-10-inducing adjuvants enhance sublingual immuno- therapy efficacy in a murine asthma model. Int Arch Al- lergy Immunol 145:152-62, 2008.