ANIMAL MODEL OF HUMAN DISEASE

Infectious and Neoplastic Respiratory Diseases Associated With Cigarette Smoking

Animal Model: Immunosuppression in the Mouse Induced by Long-term Exposure to Cigarette Smoke

Corbuted by: P. G. Hoat, PhD, D. Keast, PhD, and J. S. Mackenzie, PhD, Department of Microbiology, University of Western Australia, Nedlands, 6009, Western Australia.

Biolofic Features

Nlice exposed to their bodv-weight equivalent of 20 to 30 cigarettes per day exhibit biphasic changes in local (respiratory tract) and systemic immune function. Antibody production within the lung itself is severelyT depressed within 2 weeks of the commencement of exposure.' In contrast, regional lvmph node and systemic activity show transient enhancement as long as 16 weeks during continuous exposure 1,2 prior to eventual suppression.1 3 Cellular immune function exhibits similar temporal changes.45 This biphasic phenomenon is also demonstrable in challenge experiments involving live influenza virus and viable tumor cells.5'6 Biphasic changes in immunologic function in the mouse akin to those induced by cigarette smoke are also demonstrable following long-term exposure to industrial air pollutants.2'7 Synergism between cigarette smoking and air pollution in the etiology of respiratory disease(s) 8,9 mav therefore be explicable in immunologic terms, and air pollution per se max' induce or exacerbate respiratory disease(s) through disturbances in local immunologic function. It is also likely that the agents in tobacco smoke which produce immunosuppression are chemicallv similar to industrial air pollutants (particularly nitrogen oxides), as many of the effects on experimental animals produced by whole tobacco smoke can be mimicked by its vapor phase.'0l" It is also noteworthy that restoration of normal immunologic function in the smoking mouse occurs within 16 weeks of the cessation of exposure.'2
Publication sponsored by the Registrs of Comparative Patholog- of the Armed Forces Institute of and supported by Public Health Service Grant RR 003O1 from the Disision of Research Resources. US Department of Health, Education and Welfare, under the auspices of Universities Associated for Research and Education in Patholog-. Inc.

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Conq~rs

With Humn Dbna

Recent data suggest that immunologic function in man may also be affected by long-term inhalation of cigarette smoke. Hemagglutinationinhibiting antibody titers following immunization with killed influenza vaccines fall more rapidly in smokers than in nonsmokers,'3 provided they have little or no immunity before vaccination;"1 smokers exhibit an increased susceptibility to epidemic influenza and other respiratory infections 14-16 and an increased frequency of seroconversion after intranasal administration of live influenza vaccine;"4 lymphocytotoxic antibody production against HL-A antigens during consecutive pregnancies is less marked in smoking women than in nonsmokers;'7 smokers consistently exhibit leukocytosis;8"'-9 alveolar macrophages from cigarette smokers fail to respond to the lymphokine MIF20 and leukocyte chemotaxis is depressed in smokers.2' Silverman and colleagues 22 suggest that a transient enhancement in some aspects of T-lymphocyte function similar to that observed in the mouse 4"5 may also occur in human smokers; PHA-reactivitv and T-cell counts in the peripheral blood of smokers under 40 years of age were above normal limits.' Significantly, PHA-reactivity in smokers of 50 years and above (together with circulating IgG levels) have been shown by other workers to be reduced."
Hwna ft

Cigarette smokers exhibit enhanced prevalance rates of infectious and neoplastic disease(s), particularly at sites associated with the respiratory tract.2'" It has been recognized for several years that cigarette smoke contains a wide variety of carcinogens, and the induction of lung cancer in the smoker may result from the activity of one or more of these compounds. However, many workers have suggested that whole cigarette smoke is a more "efficient" carcinogen than would be expected on the basis of the concentration and biologic activity of its individual components. Furthermore, it is unlikely that carcinogenic tobacco tars play a significant role in the etiology of infectious respiratory disease(s) in the smoker, and consequently tobacco smoke components other than tars may also deleteriously affect the health of the smoker. It is generally accepted that under normal conditions, immunologic mechanisms operative with the respiratory tract provide the major defense against infectious disease(s); it has also been hypothesized that similar mechanisms may protect the host from the development and spread of neoplasms.x2'?l The data from the model described here suggest that immunologic function (particularly within the respiratory tract) may

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be impaired by prolonged cigarette smoking and, therefore, that cigarette-smoke-induced immunosuppression may be involved in the etiology and pathogenesis of disease(s) associated with this habit.
References
1. Thomas WR, Holt PG, Keast D: Development of alterations in the primary immune response of mice by exposure to fresh cigarette smoke. Int Arch Allergy Appi Immunol 46:481-486, 1974 2. Nulsen A, Holt PG, Keast D: Cigarette smoking, air pollution and immunity: A model system. Infect Immun 10:1226-1229, 1974 3. Thomas WR, Holt PG, Keast D: Effect of cigarette smoking on primary and secondary humoral responses in mice. Nature 243:240-241, 1973 4. Thomas WR, Holt PG, Keast D: Cellular immunity in mice chronically exposed to fresh cigarette smoke. Arch Environ Health 27:372-375, 1973 5. Chalmer J, Holt PG, Keast D: Cell-mediated immune responses to transplanted tumors in mice chronically exposed to cigarette smoke. J Natl Cancer Inst 55:1129-1134, 1975 6. Mackenzie JS: The effect of cigarette smoke on influenza virus infection: A murine model system. Life Sci 19:409-412, 1976 7. Zarkower A: Alterations in antibody response induced by chronic inhalation of SO2 and carbon. Arch Environ Health 25:45-50, 1972 8. Berry G, Newhouse ML, Turok M: Combined effect of asbestos exposure and smoking on mortality from lung cancer in factory workers. Lancet 2:476-479, 1972 9. Carnow BW, Meier P: Air pollution and pulmonary cancer. Arch Environ Health 27:207-218, 1973 10. Leuchtenberger C, Leuchtenberger R: Effects of chronic inhalation of whole fresh cigarette smoke and its vapour phase on pulmonary tumorigenesis in Snell's mice. Morphology of Experimental Respiratory Carcinogenesis. A.E.C. Symposium Series 21, USAEC Division of Technical Information, 1970, pp 329 11. Holt PG, Roberts LM, Keast D: Comparison of the effects of whole smoke and its vapour phase on immune function in the mouse. Submitted for publication, 1976 12. Thomas WR, Holt PG, Keast D: Recoverv of immune svstem after cigarette smoking. Nature 248:358-359, 1974 13. Finklea JF, Hasselblad V, Riggan WB, Nelson WC, Hammer DI, Newill VA: Cigarette smoking and hemagglutination inhibition response to influenza after natural disease and immunization. Am Rev Resp Dis 104:368-376, 1971 14. Mackenzie JS, Mackenzie IA, Holt PG: The effect of cigarette smoking on susceptibilitv to epidemic influerza and on serological responses to live attenuated and killed subunit influenza vaccines. J Hyg (Camb) 77:409-417, 1977 15. Finklea JF, Hasselblad V, Sandifer SH, Hammer DI, Lowrimore GR: Cigarette smoking and acute non-influenzal respiratorv disease in militarv cadets. Am J Epidemiol 93:451-462, 1971 16. Finklea JF, Sandifer SH, Smith DD: Cigarette smoking and epidemic influenza. Am J Epidemiol 90:390-399, 1969 17. Nymand G: Matemal smoking and immunity. Lancet 2:1379-1380, 1974 18. Friedman GD, Siegelaub AB, Seltzer CC, Feldfman R, Collen M F: Smoking habits and the leukocyte count. Arch Environ Health 26:137-143, 1973 19. Corre F, Lellouch J, Schwartz D: Smoking and leukocvte counts. Results of an epidemiological survey. Lancet 2:632-634, 1971 20. Warr GA, Martin RR: In vitro migration of human alveolar macrophages: Effects of cigarette smoking. Infect Immun 8:222-227, 1973

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21. Noble RC, Penny BB: Comparison of leukocyte count and function in smoking and nonsmoking young men. Infect Immun 12:550-555, 1975 22. Silverman NA, Potvin C, Alexander JC Jr, Chretien PB: In vitro lymphocyte reactivity and T-ell levels in chronic cigarette smokers. Clin Exp Immunol 22:285-292, 1975 23. Vos-Brat LC, Rumke PH: Immunoglobuline concentraties, PHA reacties van lvmfocyten in vitro en enkele antistof titers van gezonde rokers. Jaarb Kanker Kanker Neder 19:49, 1969 24. Royal College of Physicians of London: Smoking and Health N.W. Philadelphia, J. B. Lippincott Co., 1971 25. U.S. Public Health Service: Health Consequences of Smoking, Department of Health, Education and Welfare, Publication No. 71-7513, 1971 26. Burnet M: Immunological Surveillance. Oxford, Pergamon Press, 1970 27. Keast D: Immunosurveillance and cancer. Lancet 2:710-712, 1970