Requirements for allergen-induced airway hyperreactivity in T and B cell-deficient mice (original) (raw)

Abstract

BACKGROUND: The pathogenesis of asthma is believed to reflect antigen-induced airway inflammation leading to the recruitment of eosinophils and activation of mast cells through cell-associated IgE. Controversies persist however, regarding the relative importance of different pathogenic cells and effector molecules. MATERIALS AND METHODS: A variety of gene-targeted mice were examined for the induction of cholinergic airway hyperresponsiveness (AH), allergic airway inflammation, mucus production, and serum IgE reactivity following intratracheal challenge with a potent allergen. AH was determined using whole-body plethysmography following acetylcholine challenge. Where possible, results were confirmed using neutralizing antibodies and cell-specific reconstitution of immune deficient mice. RESULTS: T and B cell-deficient, recombinase-activating-gene-deficient mice (RAG -/-) failed to develop significant allergic inflammation and AH following allergen challenge. Reconstitution of RAG -/- mice with CD4+ T cells alone was sufficient to restore allergen-induced AH, allergic inflammation, and goblet cell hyperplasia, but not IgE reactivity. Sensitized B cell-deficient mice also developed airway hyperreactivity and lung inflammation comparable to that of wild-type animals, confirming that antibodies were dispensable. Treatment with neutralizing anti-IL-4 antibody or sensitization of IL-4-deficient mice resulted in loss of airway hyperreactivity, whereas treatment with anti-IL-5 antibody or sensitization of IL-5-deficient mice had no effect. CONCLUSIONS: In mice, CD4+ T cells are alone sufficient to mediate many of the pathognomonic changes that occur in human asthma by a mechanism dependent upon IL-4, but independent of IL-5, IgE, or both. Clarification of the role played by CD4+ T cells is likely to stimulate important therapeutic advances in treatment of asthma.

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  1. Bozic C. R., Lu B., Höpken U. E., Gerard C., Gerard N. P. Neurogenic amplification of immune complex inflammation. Science. 1996 Sep 20;273(5282):1722–1725. doi: 10.1126/science.273.5282.1722. [DOI] [PubMed] [Google Scholar]
  2. Bradding P., Feather I. H., Howarth P. H., Mueller R., Roberts J. A., Britten K., Bews J. P., Hunt T. C., Okayama Y., Heusser C. H. Interleukin 4 is localized to and released by human mast cells. J Exp Med. 1992 Nov 1;176(5):1381–1386. doi: 10.1084/jem.176.5.1381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bradding P., Roberts J. A., Britten K. M., Montefort S., Djukanovic R., Mueller R., Heusser C. H., Howarth P. H., Holgate S. T. Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol. 1994 May;10(5):471–480. doi: 10.1165/ajrcmb.10.5.8179909. [DOI] [PubMed] [Google Scholar]
  4. Broide D. H., Paine M. M., Firestein G. S. Eosinophils express interleukin 5 and granulocyte macrophage-colony-stimulating factor mRNA at sites of allergic inflammation in asthmatics. J Clin Invest. 1992 Oct;90(4):1414–1424. doi: 10.1172/JCI116008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brusselle G., Kips J., Joos G., Bluethmann H., Pauwels R. Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice. Am J Respir Cell Mol Biol. 1995 Mar;12(3):254–259. doi: 10.1165/ajrcmb.12.3.7873190. [DOI] [PubMed] [Google Scholar]
  6. Buijs J., Egbers M. W., Lokhorst W. H., Savelkoul H. F., Nijkamp F. P. Toxocara-induced eosinophilic inflammation. Airway function and effect of anti-IL-5. Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 1):873–878. doi: 10.1164/ajrccm.151.3.7881685. [DOI] [PubMed] [Google Scholar]
  7. Burd P. R., Thompson W. C., Max E. E., Mills F. C. Activated mast cells produce interleukin 13. J Exp Med. 1995 Apr 1;181(4):1373–1380. doi: 10.1084/jem.181.4.1373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Corry D. B., Folkesson H. G., Warnock M. L., Erle D. J., Matthay M. A., Wiener-Kronish J. P., Locksley R. M. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J Exp Med. 1996 Jan 1;183(1):109–117. doi: 10.1084/jem.183.1.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coyle A. J., Wagner K., Bertrand C., Tsuyuki S., Bews J., Heusser C. Central role of immunoglobulin (Ig) E in the induction of lung eosinophil infiltration and T helper 2 cell cytokine production: inhibition by a non-anaphylactogenic anti-IgE antibody. J Exp Med. 1996 Apr 1;183(4):1303–1310. doi: 10.1084/jem.183.4.1303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Daniels S. E., Bhattacharrya S., James A., Leaves N. I., Young A., Hill M. R., Faux J. A., Ryan G. F., le Söuef P. N., Lathrop G. M. A genome-wide search for quantitative trait loci underlying asthma. Nature. 1996 Sep 19;383(6597):247–250. doi: 10.1038/383247a0. [DOI] [PubMed] [Google Scholar]
  11. Doull I. J., Lawrence S., Watson M., Begishvili T., Beasley R. W., Lampe F., Holgate T., Morton N. E. Allelic association of gene markers on chromosomes 5q and 11q with atopy and bronchial hyperresponsiveness. Am J Respir Crit Care Med. 1996 Apr;153(4 Pt 1):1280–1284. doi: 10.1164/ajrccm.153.4.8616554. [DOI] [PubMed] [Google Scholar]
  12. Einarsson O., Geba G. P., Zhu Z., Landry M., Elias J. A. Interleukin-11: stimulation in vivo and in vitro by respiratory viruses and induction of airways hyperresponsiveness. J Clin Invest. 1996 Feb 15;97(4):915–924. doi: 10.1172/JCI118514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Eum S. Y., Hailé S., Lefort J., Huerre M., Vargaftig B. B. Eosinophil recruitment into the respiratory epithelium following antigenic challenge in hyper-IgE mice is accompanied by interleukin 5-dependent bronchial hyperresponsiveness. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12290–12294. doi: 10.1073/pnas.92.26.12290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Foster P. S., Hogan S. P., Ramsay A. J., Matthaei K. I., Young I. G. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med. 1996 Jan 1;183(1):195–201. doi: 10.1084/jem.183.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Franklin W., Goetzl E. J. Total absence of eosinophils in a patient with an allergic disorder. Ann Intern Med. 1981 Mar;94(3):352–353. doi: 10.7326/0003-4819-94-3-352. [DOI] [PubMed] [Google Scholar]
  16. Ganzalo J. A., Jia G. Q., Aguirre V., Friend D., Coyle A. J., Jenkins N. A., Lin G. S., Katz H., Lichtman A., Copeland N. Mouse Eotaxin expression parallels eosinophil accumulation during lung allergic inflammation but it is not restricted to a Th2-type response. Immunity. 1996 Jan;4(1):1–14. doi: 10.1016/s1074-7613(00)80293-9. [DOI] [PubMed] [Google Scholar]
  17. Garlisi C. G., Falcone A., Kung T. T., Stelts D., Pennline K. J., Beavis A. J., Smith S. R., Egan R. W., Umland S. P. T cells are necessary for Th2 cytokine production and eosinophil accumulation in airways of antigen-challenged allergic mice. Clin Immunol Immunopathol. 1995 Apr;75(1):75–83. doi: 10.1006/clin.1995.1055. [DOI] [PubMed] [Google Scholar]
  18. Garssen J., Nijkamp F. P., Van Der Vliet H., Van Loveren H. T-cell-mediated induction of airway hyperreactivity in mice. Am Rev Respir Dis. 1991 Oct;144(4):931–938. doi: 10.1164/ajrccm/144.4.931. [DOI] [PubMed] [Google Scholar]
  19. Gavett S. H., Chen X., Finkelman F., Wills-Karp M. Depletion of murine CD4+ T lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia. Am J Respir Cell Mol Biol. 1994 Jun;10(6):587–593. doi: 10.1165/ajrcmb.10.6.8003337. [DOI] [PubMed] [Google Scholar]
  20. Gavett S. H., O'Hearn D. J., Karp C. L., Patel E. A., Schofield B. H., Finkelman F. D., Wills-Karp M. Interleukin-4 receptor blockade prevents airway responses induced by antigen challenge in mice. Am J Physiol. 1997 Feb;272(2 Pt 1):L253–L261. doi: 10.1152/ajplung.1997.272.2.L253. [DOI] [PubMed] [Google Scholar]
  21. Gleich G. J., Kita H. Bronchial asthma: lessons from murine models. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2101–2102. doi: 10.1073/pnas.94.6.2101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Goldstein R. A., Paul W. E., Metcalfe D. D., Busse W. W., Reece E. R. NIH conference. Asthma. Ann Intern Med. 1994 Nov 1;121(9):698–708. doi: 10.7326/0003-4819-121-9-199411010-00011. [DOI] [PubMed] [Google Scholar]
  23. Gonzalo J. A., Lloyd C. M., Kremer L., Finger E., Martinez-A C., Siegelman M. H., Cybulsky M., Gutierrez-Ramos J. C. Eosinophil recruitment to the lung in a murine model of allergic inflammation. The role of T cells, chemokines, and adhesion receptors. J Clin Invest. 1996 Nov 15;98(10):2332–2345. doi: 10.1172/JCI119045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Grünig G., Corry D. B., Leach M. W., Seymour B. W., Kurup V. P., Rennick D. M. Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J Exp Med. 1997 Mar 17;185(6):1089–1099. doi: 10.1084/jem.185.6.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hamelmann E., Oshiba A., Schwarze J., Bradley K., Loader J., Larsen G. L., Gelfand E. W. Allergen-specific IgE and IL-5 are essential for the development of airway hyperresponsiveness. Am J Respir Cell Mol Biol. 1997 Jun;16(6):674–682. doi: 10.1165/ajrcmb.16.6.9191469. [DOI] [PubMed] [Google Scholar]
  26. Hamelmann E., Vella A. T., Oshiba A., Kappler J. W., Marrack P., Gelfand E. W. Allergic airway sensitization induces T cell activation but not airway hyperresponsiveness in B cell-deficient mice. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1350–1355. doi: 10.1073/pnas.94.4.1350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hogan S. P., Mould A., Kikutani H., Ramsay A. J., Foster P. S. Aeroallergen-induced eosinophilic inflammation, lung damage, and airways hyperreactivity in mice can occur independently of IL-4 and allergen-specific immunoglobulins. J Clin Invest. 1997 Mar 15;99(6):1329–1339. doi: 10.1172/JCI119292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Jose P. J., Griffiths-Johnson D. A., Collins P. D., Walsh D. T., Moqbel R., Totty N. F., Truong O., Hsuan J. J., Williams T. J. Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. J Exp Med. 1994 Mar 1;179(3):881–887. doi: 10.1084/jem.179.3.881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Juhlin L., Michaëlsson G. A new syndrome characterised by absence of eosinophils and basophils. Lancet. 1977 Jun 11;1(8024):1233–1235. doi: 10.1016/s0140-6736(77)92440-0. [DOI] [PubMed] [Google Scholar]
  30. Kaplan M. H., Schindler U., Smiley S. T., Grusby M. J. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996 Mar;4(3):313–319. doi: 10.1016/s1074-7613(00)80439-2. [DOI] [PubMed] [Google Scholar]
  31. Kita H., Gleich G. J. Chemokines active on eosinophils: potential roles in allergic inflammation. J Exp Med. 1996 Jun 1;183(6):2421–2426. doi: 10.1084/jem.183.6.2421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kitamura D., Roes J., Kühn R., Rajewsky K. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature. 1991 Apr 4;350(6317):423–426. doi: 10.1038/350423a0. [DOI] [PubMed] [Google Scholar]
  33. Kopf M., Brombacher F., Hodgkin P. D., Ramsay A. J., Milbourne E. A., Dai W. J., Ovington K. S., Behm C. A., Köhler G., Young I. G. IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses. Immunity. 1996 Jan;4(1):15–24. doi: 10.1016/s1074-7613(00)80294-0. [DOI] [PubMed] [Google Scholar]
  34. Korsgren M., Erjefält J. S., Korsgren O., Sundler F., Persson C. G. Allergic eosinophil-rich inflammation develops in lungs and airways of B cell-deficient mice. J Exp Med. 1997 Mar 3;185(5):885–892. doi: 10.1084/jem.185.5.885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kotsimbos T. C., Ernst P., Hamid Q. A. Interleukin-13 and interleukin-4 are coexpressed in atopic asthma. Proc Assoc Am Physicians. 1996 Sep;108(5):368–373. [PubMed] [Google Scholar]
  36. Kurup V. P., Ramasamy M., Greenberger P. A., Fink J. N. Isolation and characterization of a relevant Aspergillus fumigatus antigen with IgG- and IgE-binding activity. Int Arch Allergy Appl Immunol. 1988;86(2):176–182. doi: 10.1159/000234568. [DOI] [PubMed] [Google Scholar]
  37. Kühn R., Rajewsky K., Müller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991 Nov 1;254(5032):707–710. doi: 10.1126/science.1948049. [DOI] [PubMed] [Google Scholar]
  38. Leung D. Y., Martin R. J., Szefler S. J., Sher E. R., Ying S., Kay A. B., Hamid Q. Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med. 1995 Jan 1;181(1):33–40. doi: 10.1084/jem.181.1.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Lin R. Y., Lazarus T. S. Asthma and related atopic disorders in outpatients attending an urban HIV clinic. Ann Allergy Asthma Immunol. 1995 Jun;74(6):510–515. [PubMed] [Google Scholar]
  40. Locksley R. M. Th2 cells: help for helminths. J Exp Med. 1994 May 1;179(5):1405–1407. doi: 10.1084/jem.179.5.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Mehlhop P. D., van de Rijn M., Goldberg A. B., Brewer J. P., Kurup V. P., Martin T. R., Oettgen H. C. Allergen-induced bronchial hyperreactivity and eosinophilic inflammation occur in the absence of IgE in a mouse model of asthma. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1344–1349. doi: 10.1073/pnas.94.4.1344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
  43. Möller G. M., de Jong T. A., van der Kwast T. H., Overbeek S. E., Wierenga-Wolf A. F., Thepen T., Hoogsteden H. C. Immunolocalization of interleukin-4 in eosinophils in the bronchial mucosa of atopic asthmatics. Am J Respir Cell Mol Biol. 1996 May;14(5):439–443. doi: 10.1165/ajrcmb.14.5.8624248. [DOI] [PubMed] [Google Scholar]
  44. Nakajima H., Gleich G. J., Kita H. Constitutive production of IL-4 and IL-10 and stimulated production of IL-8 by normal peripheral blood eosinophils. J Immunol. 1996 Jun 15;156(12):4859–4866. [PubMed] [Google Scholar]
  45. Nakajima H., Sano H., Nishimura T., Yoshida S., Iwamoto I. Role of vascular cell adhesion molecule 1/very late activation antigen 4 and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 interactions in antigen-induced eosinophil and T cell recruitment into the tissue. J Exp Med. 1994 Apr 1;179(4):1145–1154. doi: 10.1084/jem.179.4.1145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Nonaka M., Nonaka R., Woolley K., Adelroth E., Miura K., Okhawara Y., Glibetic M., Nakano K., O'Byrne P., Dolovich J. Distinct immunohistochemical localization of IL-4 in human inflamed airway tissues. IL-4 is localized to eosinophils in vivo and is released by peripheral blood eosinophils. J Immunol. 1995 Sep 15;155(6):3234–3244. [PubMed] [Google Scholar]
  47. Oettgen H. C., Martin T. R., Wynshaw-Boris A., Deng C., Drazen J. M., Leder P. Active anaphylaxis in IgE-deficient mice. Nature. 1994 Aug 4;370(6488):367–370. doi: 10.1038/370367a0. [DOI] [PubMed] [Google Scholar]
  48. Ohara J., Paul W. E. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. doi: 10.1038/315333a0. [DOI] [PubMed] [Google Scholar]
  49. Oshiba A., Hamelmann E., Takeda K., Bradley K. L., Loader J. E., Larsen G. L., Gelfand E. W. Passive transfer of immediate hypersensitivity and airway hyperresponsiveness by allergen-specific immunoglobulin (Ig) E and IgG1 in mice. J Clin Invest. 1996 Mar 15;97(6):1398–1408. doi: 10.1172/JCI118560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Rankin J. A., Picarella D. E., Geba G. P., Temann U. A., Prasad B., DiCosmo B., Tarallo A., Stripp B., Whitsett J., Flavell R. A. Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7821–7825. doi: 10.1073/pnas.93.15.7821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Robinson D. S., Hamid Q., Ying S., Tsicopoulos A., Barkans J., Bentley A. M., Corrigan C., Durham S. R., Kay A. B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992 Jan 30;326(5):298–304. doi: 10.1056/NEJM199201303260504. [DOI] [PubMed] [Google Scholar]
  52. Robinson D. S., Tsicopoulos A., Meng Q., Durham S., Kay A. B., Hamid Q. Increased interleukin-10 messenger RNA expression in atopic allergy and asthma. Am J Respir Cell Mol Biol. 1996 Feb;14(2):113–117. doi: 10.1165/ajrcmb.14.2.8630259. [DOI] [PubMed] [Google Scholar]
  53. Rothenberg M. E., MacLean J. A., Pearlman E., Luster A. D., Leder P. Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia. J Exp Med. 1997 Feb 17;185(4):785–790. doi: 10.1084/jem.185.4.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Schumacher J. H., O'Garra A., Shrader B., van Kimmenade A., Bond M. W., Mosmann T. R., Coffman R. L. The characterization of four monoclonal antibodies specific for mouse IL-5 and development of mouse and human IL-5 enzyme-linked immunosorbent. J Immunol. 1988 Sep 1;141(5):1576–1581. [PubMed] [Google Scholar]
  55. Seaton A., Godden D. J., Brown K. Increase in asthma: a more toxic environment or a more susceptible population? Thorax. 1994 Feb;49(2):171–174. doi: 10.1136/thx.49.2.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Shelhamer J. H., Levine S. J., Wu T., Jacoby D. B., Kaliner M. A., Rennard S. I. NIH conference. Airway inflammation. Ann Intern Med. 1995 Aug 15;123(4):288–304. doi: 10.7326/0003-4819-123-4-199508150-00008. [DOI] [PubMed] [Google Scholar]
  57. Shimura S., Andoh Y., Haraguchi M., Shirato K. Continuity of airway goblet cells and intraluminal mucus in the airways of patients with bronchial asthma. Eur Respir J. 1996 Jul;9(7):1395–1401. doi: 10.1183/09031936.96.09071395. [DOI] [PubMed] [Google Scholar]
  58. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  59. Shirakawa T., Enomoto T., Shimazu S., Hopkin J. M. The inverse association between tuberculin responses and atopic disorder. Science. 1997 Jan 3;275(5296):77–79. doi: 10.1126/science.275.5296.77. [DOI] [PubMed] [Google Scholar]
  60. Stellato C., Collins P., Ponath P. D., Soler D., Newman W., La Rosa G., Li H., White J., Schwiebert L. M., Bickel C. Production of the novel C-C chemokine MCP-4 by airway cells and comparison of its biological activity to other C-C chemokines. J Clin Invest. 1997 Mar 1;99(5):926–936. doi: 10.1172/JCI119257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Sylvestre D. L., Ravetch J. V. Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science. 1994 Aug 19;265(5175):1095–1098. doi: 10.1126/science.8066448. [DOI] [PubMed] [Google Scholar]
  62. Walker C., Virchow J. C., Jr, Bruijnzeel P. L., Blaser K. T cell subsets and their soluble products regulate eosinophilia in allergic and nonallergic asthma. J Immunol. 1991 Mar 15;146(6):1829–1835. [PubMed] [Google Scholar]
  63. Wallaert B., Desreumaux P., Copin M. C., Tillie I., Benard A., Colombel J. F., Gosselin B., Tonnel A. B., Janin A. Immunoreactivity for interleukin 3 and 5 and granulocyte/macrophage colony-stimulating factor of intestinal mucosa in bronchial asthma. J Exp Med. 1995 Dec 1;182(6):1897–1904. doi: 10.1084/jem.182.6.1897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Wardlaw A., Geddes D. M. Allergic bronchopulmonary aspergillosis: a review. J R Soc Med. 1992 Dec;85(12):747–751. doi: 10.1177/014107689208501212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Watanabe A., Mishima H., Renzi P. M., Xu L. J., Hamid Q., Martin J. G. Transfer of allergic airway responses with antigen-primed CD4+ but not CD8+ T cells in brown Norway rats. J Clin Invest. 1995 Sep;96(3):1303–1310. doi: 10.1172/JCI118165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Weiss K. B., Gergen P. J., Hodgson T. A. An economic evaluation of asthma in the United States. N Engl J Med. 1992 Mar 26;326(13):862–866. doi: 10.1056/NEJM199203263261304. [DOI] [PubMed] [Google Scholar]