Tobacco Documents Online

0. .as In- ~is Iat ?r- ea1 Nct mal 11 'the hne , ing. art- No. 4' CHAPTER 7 Al llergy ting ttcet

C~onten#s Introduction .......................................... Antigenic Properties ............. ............ ............ Skin Testing ........................................... Additional Immunological Effects ....................... Effect on the Immune Response .............. ........... Irritant and Pharrnacol'ogic Effects ...................... Clinical Allergy ........................................ Summary .............................. References .............................................. Page 103 . 104 105, 107 108'. 109 . 1110 1 111 ' 11112 rmu

INTRODUCTION As early as 1886 reference was made to an entity called "tobacco asthma" (64)., Subsequently, controversy has arisen over whether tobacco srnoking, causes clinical allergy (61) and whether such tobacco alliergy is associated with the major smoking-related dis- eases (25, 69). In 1957; Silvette, et al. (64) reviewed more than 100 papers con- cerned with "'the immunological aspects of tobacco and smoking." They concluded that inadequate animal studies had been performed in this area. Referring to.clinical studies, they observed: "'. . . virtu- ally all reported clinical investigation has been limited to d'etermi- nations of cutaneous sensitivity to tobacco extt'racts ; and it must be regretfully admitted't'hat much of this published work is equivocal, uncritical, and inadequately controlled."' Such criticism~ is also applicable to many: studies published'! since then. Epidemiologic studies designed to determine the prevalence of tobacco allergy have not been carried out; hence, it is difficult to evaluate the magnitude of the problem. Allergy may be defined as a specifi'c, alteration in response medi- ated by an antigen-antibody reaction. When a hereditary suscepti- bility to allergic illness is present, the term atopy is used. For ex- ample, hay fever and asthma are atopic diseases. Thereil& no single test or observation whi~ch can be used to de- termine whether ai substance may be responsible for allergic dis- ease ;, however,, f ulfillment of' the following criteria constitutes evi~- dence for such a relati,onship : 1. Demonstration that the substance is antigenic, Le:, capable of stimulating,the production of antibody and then reacting withi the antibody. 2.. Demonstrationthat, upon exposure to the substance,, signs and symmptoms simulating an allergic reaction are elieited whichh disappear upon its removall 3. D!emonstration that the immunologic event is related to the clinical event. Recent advances in the understanding of'irnmunological reactions as well as in the methodology of'immunology are now being applied 1os

to problems of clinical allergy. For example, Ishizaka (37), using radioimmunoelectrophoresis, recently reported that the so-called "allergic antibody" (reagin, skin-sensitizing antibody (SSA), atopic antibody) belongs to~ a new class of immunoglobulins, IgE. Although the skin test remains a simple and definitive method of demonstrating reagins in the allergic patient, there are many vari- ables involved in this technique which must be carefully weighed when interpreting; test results. In the area of tobacco skin testing, such variables include: diffierences in antigenic content of the test extract, diifferences in, route of administration, and heterogeneity of test groups. ANTIGENIC PROPERTIES Tobacco leaf contains a complex mixture of chemical components inchzding : celluloses, starches, proteins, sugars, alkaloids, pectic substances, hydrocarbons, phenols, fatty acids, isoprenoids, sterols, and inorganic minerals (69). Theoretically, relatively few of'these substances should be antigenic. Tobacco~extracts of different compo- sition result from dlifferences in tobacco types and species, process- ing of tobacco, and preparation of the extract. Harkavy (26) has shown in some patients a differential skin reactivity to extracts from different types of tobacco. Cbltoiu, et al. (9) reported that 13 different antigens capable of inducing; precipitins in rabbits have been isolated1from tobacco pollen. Chu, et al. (7) prepared aqueous extracts of five commercial tobacco products which stimulated anti body formationi in rabbits. Ti he antigens contained in the extracts included both proteins and polysaccharides and had molecular weights ranging from, 20;000 to 60,000: Silvette, et al. (64) reviewed several papers dealing with the immunology of nicotine and concluded that nicotine was nonanti- genic. Harkavy (25),, who performed some of the earliest studies on the antigenicity of nicotine, could not exclude the possibility that nicotine may act as a hapten. A hapten is a compound which, a1- thoughnot antigenic by itself, reacts with antibody andl conveys antigenic speeificity when combined with another compound.. With pyrolysis many of the tobacco constituents undergo reac- tions involving, oxidation, dehydrogenation, cracking,, rearrange- ment„ and condensation (69). Many new comrpounds are formed. Pipes (51) demonstrated, through exhaustion of passive transfer reactivity ini skin sites, that allergy to, tobacco smoke in man, is dis- tinct from that of allergy to tobacco leaf: Tobacco smoke exhausted reactivity in sites injected with tobacco smoke sensitized serurn; reactivity was reduced but not exhausted with tobacco extract. The converse was true with passive transfer sites of tobacco-sensitizedi serum; tobacco extracts abolished allergic reactivity whereas to- r04

bacco smoke extract produced a diminutioni but not totall exl.iaustion:. He concluded that it would be useful to test human suba ects for both tobacco leaf and tobacco smoke sensitivity. Kreis„ et al. (3'9)': have. speculated that tobacco leaf antigenieity may be lost with pyrolxsis.. CaItoiia, et ah (9), recently emphasized the importance of remov- ing all irritants from~ test extracts. Dn a clinical setting, allergy too tobacco additives such as menthol ha& also been suspected (47). SKIN TESTING 7e ti, es at al- iys ~c- ~e- edL Fer iis- tedi rm;; 'he ;ed to- Intracutaneous injection of test antigen is a widely usedi method of skin testing. Patch tests have also beem used in cases of suspected contact dermatitis. Roseni (54)', has observed that skin testing does not accurately duplicate the xnost common route of exposure to tobacco, i.e., tobacco smoke inhalation.. For those involvedl in the production of tobacco prodhzcts, inhalat'ioni of tobacco dust or direct contact with tobacco may play important roles in sensitization (9);. The extensive literature on cutaneous sensitivity to tobacco ex- tracts includes comparisons of the.prevalence of' positive skin reac- tions in different groups, such as "not7mal"nonsmoking adults(17,. 68), "'normalP''smokers (17, 33)~, allergic patients (59, 76), children (41, 50), tobacco workers (6„9), and patients with~ specific diseases, e.g., thromboangiitis obliterans (28, 73). Harkavy reportedl on, tobacco skin reactions in several different groups of patients (34). Many of the apparently discordant results in some of these, reports can be traced to failure to compare similar populations or to control for differences in the test antigen or in the method of testing. Sulzberger (66) studied the different types of skin reactions pro- duced by intracutaneous inj eetion of' denicotinized tobacco extract.. Three types of positive skin responses were observed: eczematous reactions ; immediate wheal-and-flare reactions ;; and late reactions, probably of the tuberculin type. The: wheal-anMare response has beeni by far the predominant type (42). This immediate wheal-and-fiare response! is a specific immune re- action (6k) largely mediated by IgD: Patterson (48): recently pro- posed a simplified model explaining the mechanism of action of the skin, sensitizing antibody (SSA). "Subsequent to stimulation of the: animall by antigen, SSA are produced by cells of the lymphoid sys- tem possibly located in the alimentary and respiratory tract. ... The SSA so produced are secret'ed! in such a way that they reach the cir- culatiion, where: circulating, cells, predominantly basophilic leuka cytes; are sensitized', by attachment of the SSA to the cell'surfaee: In addition, the SSA also: leave the, vascular compartment and sen- sitize rnediator-releasing cells in tissues. The tissue cells are pri- marily mast celIs ... The immediate-type allergic reaction occurs 105 ~,,

when antigen is introduced into the individu~ali sensitized by SSA,either by transfer of antigenic molecules, through the respiratory or alimentary mucosal surface or by injection into the skin or vascular system.. The antigens reach the antibody on the surface of the mast cellls and initiate the intracellular events that result in mediator re- lease from the cells." The actions of these mediators include smooth muscle contraction, vasodilation„and increased capillary permeabil- ity which can produce such clinical pictures as hay fever, asthma, and generalizedl anaphylaxis:. Until recently, direct skin testing and the passive transfer test (Prausnitz-Kustner reaction): were the on]y methods of studying IgE mediated responses. In the passive transfer test, serum from, an allergic patientis injected into the skin of' a normal! subject. After a suitable interval the antigen is injected into the prepared site and adjacent normal skin. In a positive response, cutaneous reactivity is transferred to the.normal subject at the! injection~ site. The absence, of' a positive response in nearby normal skin excludes nonspecific irritationi as a cause of the response and shows that the normal subject is not himself allergic to the antigen. Harkavy and W'itebsky (34), found andl selectively absorbed' tobacco reagins in patients showing multiple sensitivities. This, se- lective absorption documented the immunologic mechanism of then skin reaction., Passive transfer of the SSA was also reported by P'eshkin, and Landay(50~) and by Lirna and Rocha (41):. Lowelli (.4'3:) stated, "The individual possessing skin-sensitizing antibody to the tobacco extract may be regarded as unequ2vocally allergic to the extract...... Despite the inability of Sulzberger and Feit (87),' to: demonstrate tobacco reagins in their skin test positive patients; several investigators have found them (26, 50, 75). Harkavy (23) biopsied urtiicarial wheals after intradermal injec- tion of tobacco extract and foundl a local eosinophilia. He felt that this helped confirmithe allergic mechanism of the positive skin test. He also biopsied the site of' a delayedi skin reaction to tobacco and foundlan eczemat'ous type of response.. The delayed type hypersensitivity reactioni is manifested by in,- duration and erythema developing,within 2:4 to 48 hours after injec- tion of antigen. The absence of' response ini the first 6 to 8 hours after exposure to antigeni helps exclude an Arthus reaction, which is also a slowly evolviing allergic response. Serum antibodies are nott involved in the initiation of delayed type hypersensitivit'y; rather, the initial step is thought to involve interactioniof antigen and spec- ialized lymphocytes(1'0, 11)~. Contact dermatitis~ is thought, to be very nearly a pure type, dlelayed' hypersensitivity reaction (10, 11) ., The foregoing discussion has hig)ilighted the: studies concerning cutaneous sensitivity to tobacco extracts. Despite the complexities andl contradictions, numerous workers agree that tobacco extract 106

(leaf or smoke) is antigenic and' can sensitize (2, 7, 9, 18; 26; 43; 60; 52, 64,, 66, 76) . Silvette, et al. (64) concluded!, "It is, indeed', beyond question that allergy to tobacco extracts, presumably atopic in na- ture, is an established fact. ..." Lowell (43) observed that, in most instances, skin reactivity to an, extract of tobacco actually means the presence of'allergy in some degree to something in the extract. Arrneni and Cohen (2), Harkavy and Perlman (31)I, and Popescu, et al. (52)1 observed! that tobacco extract is weakly antigenic. Armen and' Cohen (2) were abl'e to sensitize rabbits to tobacco proteins only after absorbing the pro- tein to alurninum hydroxide, which served' as' an adjuvant. Even though a positive skin test to tobacco extract may be due to a specific allergic reactions the interpretation of such a positive test in a given patient or group of patients poses problems, since sen- sitivity to a battery of antigens has been demonstrated' in indiuid uals who are entirely free from allergic symptoms upon exposuree to the antigens. Rosen (54) statedl that this lack of correlation be- tween positive skin tests and clinical symptoms is great'er, for to- bacco thani for other antigens such as pollens,, dusts, and feathers. He and others have emphasized that the skin test has value only when correlated with clinical evidence. Analysis of'skin test studies in nonsmokers (64) shows that ap- proximately 15 percent of such "'healt'hy"' individuals give positive reactions to tobacco extracts. Some studies of smokers reporting a 30 percent or more prevalence of skin sensitivity to tobacco ex- tract (33;, 43) have considered patients withi multiple sensitivities, including that to tobacco. Atopic individuals have been noted, to have a greater prevalence of skin sensitivity to, tobacco than, non- atopics (64) ; hence, in some studies an excess of' atopic patients may account for al substantial part of' the elevated prevalence of tobacco skin sensitivity reported for smokers: Several workers have sought to use the skin test as a screening device for indicating, an unusual susceptibility to the adverse effects of tobacco. DeCrinis, et al. ('13)1, Font'ana (17), and, Redisch (53) have reported that patients with positiiae skin tests to tobacco ex- tracts were more likely to have an adverse vascular response to tobacco as indicated by a fall in peripheral skin temperature on smoking. More recent studies have shown that a decrease in skin temperature with smoking is al reproducible response to nicotine found in "normal" " individuals and does not appear to be confined to a specific group of smokers (1, 56, 70). ADDITIONAL IMMUNOLOGICAL EFFECTS. Additional evidence is available toisupport the view that tobacco indhces immunologic changes in, man and animals. Armen and G'1

Cohen (2); C'hu,, etal. (;7)~, Harkavy and P'erlknan (31)~,and Zuss-man (76) induced precipitin formation in animals sensitized to tobacco extract. Kreis, et al. (39) studiedlprecipitation reactions in, 657 hospitalized patients, many of whom were suffering from tu- berculosis or lung cancer. A precipitation reaction between the pa- tients''sera andlal commercial tobacco extract was found in 62.5 per= cent of the patients. Chu, et al. (7), using the same antigens as those ernployed to stimulate precipitin fmrmationi in rabbits, found serum antibodies in 40percent of a group of smokers which precipi- tatedl specificially with, the tobacco antigens. Only 7 percent of a group,of nonsmokers demonstrated, these ant'ibodies. Savel (59) studied! eight nonsmoking, allergic individuals who; developed immediate upper respiratory discomfortafter being; ex- posed to cigarette smoke. As measured by: the uptake of tritia,tedd thymidine, the lymphocytes of these individuals were stimulated by cigarette smoke;, while "normal" lymphocytes were depressed. The authorstated, t'hatthet correlat'ion, of this test with specific forms of clinical allergy: remains uncertain. Some investigators have observed abnormal laboratory test re- sults in smokers as compared to nonsmokers, which may indicate an allergic response in the former group. Schoen and Pizer (60)~ de- scribed a smoking woman, who demonstrated a striking blood eosino- philia while smoking cigarettes. U'pon cessation of smoking, the eosinophil count returned promptly to normal levels. Resumption of smoking was associated with a return of the eosinophilia. Heiskells et al. (36), found al significant increase in, C-reactive protein and an abnormal seroflocculant for ethyl cholledienate in smokers as com- pared to nonsmokers. Plasma; histaminase levels were reportedl by Kameswaran, et all (38): to:be elevated in smokers. Experimental animal sensitization to tobacco: was reported by Friedlander, et al. (19) in male rat's: Harkavy (29) confirmed these results in male rats and also obtained positive S'chultz-Dale reac- tions in the sensitized animals ; however, female rats failedl to dem- onstrate this sensitizat'iom. Harkavy (24) reported cardiac histo- logical abnormalities in three rabbits sensitizedl with denicotinizedl tobacco extracts. The abnormalities found ini the three rabbits, re- spectively, included: intimal proliferation, focal fragmentation of the, internal elastic membrane, and' loss of smooth muscle fibers in the media of a branch of a coronary artery; focall intimal prolifera- tion and fibrinoid alterations, in the media of a small coronary ves- sel ; and a: focus of rnyocardiall fibrosis and' necrosis. EFFECT ONI TH'K IMMUNE RESPONSE The effect of tobacco oni the immune response has received some attention. Early studies in rabbits suggested that tobacco smoke re- , U8

! f z e tarded the, production of agglutinins in rabbits immunized against typhoid (14). A variety of observations indicate that ingestion of antigenic materiall by the macrophage rnay be an essential step in the immune response (3). Btu,ni (5) found that cigarette smoke suppressed phagocytosis in rabbits. Green and Carolin (20)i performed in nitro studies in rabbit alveolar macrophages and observed that cigarette smoke inhibited the capacity of these cells to inactivate bacteriaL Harris; et al. (35), reported no differences in the phagocytic ability of macrophages taken from human, smokers and nonsmokers, but he also concluded that his data neither contradicted nor supported Green's work. Cohen and Cline (&'), while noting,that macrophages from smokers had normal phagocytic capacity, demonstrated sub- optimal macrophage function in an environment of low O',, tension, a state found' more frequently in smokers than nonsmokers. Max- well, et al. (45), using guinea pigs, found that smoke exerted no effect on phagocytosis;, nevertheless,, smoke seemed to: impair the phagocytes'' ability to inact'ivate bacteria. Nicotine has been shown by Meyer,, et al. (46) to exert ai depressant effect on sheep pulmo- nary alveolar macrophage respiration and ATPase activity. Re- cently, Yeager (74)i reported that water soluble constituents of cigarette smoke depress protein-synthesis in rabbit alveolar macro- phages in vitro,Lewis, et al. (40) found that cigarette smoking had a suppressive act'ion, on, secretory IgA production in normal subj ects but not in subjects with chronic respiratory disorders. Vos-Brat and Rumke (71)i recently reportedi that IgG serum concentratiions and, the :~e- sponse of lymphocytes to phytohemagglutinin w~eresignificantlylower in smokers thani nonsmokers. A number of' investigators have reported increased rates of res- piratory iillnesses among cigarette smokers (70). Finklea,, et a1L (16')' studied antibody response in 289 volunteers after the 1968' Hong Kong,inliuenza epidemic. They reportedla significant decrease among cigarette smokers in the persistence of hernagg)'utinatibni in- liibition antibody after natural infection or vaccination with A_., anta'igens.Theypostulated that thisantibody defiicit among cigarette smokers might be related to increased illness during influenza out- breaks: IRRITANT' AND~ PHARIVIACOLOGIC EFFECTS As Lowell (43) has emphasized, the pharmacolbgic., irritant, andd allergic effects of tobacco~ are difficult to distingu2sh. Acrolein and acetaldbhyde are potent irritants foundl in tobacco smoke, which, as demonstrated in animali studies, are capable of releasing chemical mediators such as histamine (58)!. The inhalation of tobacco smoke . io,

causes bronchial' constriction, mucus hypersecretion,, and ciliary stasis (57)n in man, all of'which can contribute to a clinical picture indistinguishable from an allergic reaction. Several authors (4.4, 61, 63) share Sherman's (62) view that "... tobacco smoke is an im- portant secondary factor in precipitating, allergic symptoms through its action as a nonspecific irritant." Speer (65)' recently compared the subjective responses of twa groups of nonsmokers to tobacco srnoke exposure., One group of 191 patients suffered' from documented allergies:, In one-sixth of these patients a positive skin test to tobacco extract was found; but only a few patients were seen~ with objective symptoms which could be traced to tobacco smoke. The other group of 250 patients had no historyof'allergy, and was studied!by q,u~estionnaire only. Eye irrita- tion, nasal symptoms, headache, and cough were common in both groups. Speer concluded that these effects of tobacco smoke were irritative rather than allergic in origin. The data presented ini this study demonstrate that tobacco smoke can contribute to the, dis- comfort of many individuals ; they do not rule out a possible con- tribution from allergic reactions. Harkavy (30)eited experimental data distinguishing allergiiec effects f'romm pharmacologic effects of smoking such, as increasedd heart rate and decreased skin temperature:, Additional studies are needed' to separate the pharmacologic, ir- rit'ant, and' allergic effect's of tobacco srnoke: CLIIrTICAL ALLERGY It is important to understand what role tobacco and tobacco smoke may play in clinical allergy because many individuals are exposed'. to them in varying concentrations throughout the year. A variety of'conditions have been ascribed to allergic rnanifesta- tions toward tobacco leaf or smoke including : asthma, rhiniti's, urticaria, angioneurotie edema (giant hives), contact dermat'iti's, migraine headache, gast''rointestinali sy~:xnptoms„ and various cardia vascular disturbances (64) ; however, some case reports are lacking in documentation (4, 49). A small group of patients having, cutane- ous sensitivity to tobacco and showing complete disappearance of symptoms when free from exposure to tobacco were reported by Rosen and Levy (55). Included in this group were cases of asthma and urticaria. Studies of atopic indivi'duals have revealed a, group of nonsmoking patients with cutaneous sensitivity to tobacco who develbped clinical syrnptoms upon exposure to tobacco smoke (56; 76)~. In none of these.studies (54, 59, 76), have detailed immunologic investigations, attempting to link clini'cal and immunologic events, been performed. Lowell (43) reviewed case reports of contact dermatitis to to- rM