thealtered reactivity of mice after inoculation with ... · rine (28), acute heat stress (28),...

THE ALTERED REACTIVITY OF MICE AFTER INOCULATIONWITH BORDETELLA PERTUSSIS VACCINE'

LEON S. KIND

Department of Microbiology, University of California School of Medicine, San Francisco, California

CONTENTSI. Introduction............................................................................. 173

II. Sensitivity to Histamine ................................................................. 173A. Factors Influencing the Production of Histamine Sensitivity after Pertussis Inocula-

tion............................................................................. 1741. Age of mice........................................................................ 1742. Sex of mice ........................................................................ 1743. Strain of mice..................................................................... 1744. Vaccine............................................................................ 174

B. Unusual Dose-Response Curve of Histamine in Pertussis-Inoculated Mice.............. 175III. Sensitivity to Serotonin.................................................................. 175IV. Sensitivity to Anaphylaxis ............................................................... 176

A. Passive Anaphylaxis.................................................................. 176B. Active Anaphylaxis................................................................... 176

V. Pertussis Vaccine and the Adrenal Gland................................................. 177VI. Additional Biological Effects of B. pertussis.............................................. 178VII. Hypotheses.............................................................................. 176VIII. References............................................................................... 179

I. INTRODUCTION II. SENSITIVITY TO HISTAMINE

For many years the effects of bacterial inocu- Parfentjev and Goodline (4) were the first tolations have been described chiefly in terms of the report that mice injected with pertussis vaccineantibody response of the host. Recent investiga- became more susceptible to the lethal effects oftions, however, have indicated that nonspecific histamine. This finding has been confirmed manychanges in resistance to infection can follow the times, the LD60 of histamine in pertussis inocu-injection of various bacterial products into a lated mice being Ho to hoo the LD60 of thissuitable animal (1-3). Perhaps the most unusual amine in unvaccinated animals. Malkiel andand most dramatic modifications of response oc- Hargis (12) stated that Brucella aborts vaccinescur in mice injected with BordeteUa pertus8t also increase the susceptibility of mice to hista-vaccine. These animals become exceedingly sus- mine but negative results were obtained with thisceptible to the lethal effects of histamine, vaccine by Abernathy and Spink (23). Bordetellaserotonin, anaphylaxis, and gram-negative bac- parapertussis, Bordetella bronchiseptica, and Hae-terial vaccines as well as to other agents and con- mophilus influenzae (30, 31) do not sensitize miceditions listed in table 1. It should be noted, .htine; Escherichia coli, Shigela dysenteriaehowever, that the pertussis-inoculated mouse isnot a generally debilitated animal susceptible to (11), Sanmonela typhosa (4, 31), Salmonellaall forms of stress. It is no more sensitive than paratyphi, and Neiera cahalis (31) are like-normal animals to the lethal effects of epineph- wise ineffective. Rats can be sensitized to hista-rine (28), acute heat stress (28), methacholine mine (30, 32) but guinea pigs (30, 33) and rabbits(28), carbaminoylcholine (11), and 48/80 (a (33) show no increase in susceptibility after thehistamine liberator) (23, 29). administration of pertussis vaccine. Procedures

'This work was supported in part by Research and conditions other than pertussis inoculation

Grant E-2360 from the Institute of Allergy and which also sensitize mice to histamine are adre-Infectious Diseases of the National Institutes of nalectomy (34, 35), increasing age (36), andHealth. Sarcoma 180 (37).

173

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174 LEON S. KIND [VOL. 22

TABLE 1 man's report on sex differences in the response ofSituations and materials to which pertussis- pertussis-inoculated mice to histamine, most

inoculated mice possess an enhanced sensitivity investigators in this field have employed females

Increased Susceptibility References in their experiments. In view of recent mouseshortages, however, it should be pointed out that

Histamine...................... 4 males will serve equally well for most purposes.Serotonin...................... 5-9 In a recent publication (7), the LD50 of histamineAnaphylaxis .................... 1G15 base in male pertussis-inoculated TumblebrookPertussis vaccine ............... 11,16, 17 Farm mice was 3 mg per kg as compared withFractions of Bordetella pertussi. 17 915 mg per kg in uninoculated animals.Living organisms.3,18-20 S. Strain of mice. It is evident from the experi-Gram-negative vaccines......... 10,11aEndotoxins ..................... 21-23 ments of Munoz and Schuchardt (38) that strainsIrradiation ..................... 24 of mice differ greatly in the degree of histamineReduced atmospheric pressure... 25 sensitivity which appears after pertussis inocula-Cold stress ..................... 26 tion. Pertussis-injected, histamine-resistant micePeptone........................ 27 may still show an enhanced susceptibility to the

lethal effects of serotonin (5) and anaphylaxis

A. Factors Influencing the Production of 4. Vaccine. Vaccines prepared from phase I B.Histamine Sensitivity after Pertussis

4*

Vacie Vacie prprdfompaeIBHtIneoSensitivity afe erusspertussis organisms sensitize mice to histamine;Inoculation vaccines made from phase IV organisms are in-

1. Age of mice. Kind (11) reported that the effective (10, 11,41). Investigators have producedLD60 and (19/20 confidence limits) of histamine detectable sensitization with 0.3 billion (39), 0.5after pertussis inoculation were 54 (31 to 92) billion (38), and 0.8 billion (30) phase I B. per-mg per kg for 10 to 15 g mice and 17 (12 to 23) tussis cells. The degree of sensitization can be en-mg per kg for 20 to 30 g animals. Munoz and hanced by increasing the dose of vaccine (30, 38,Schuchardt (38) found that 3 week old mice 39). Resistant strains of mice, however, cannot(12 1 g weight) of a particular strain were be made histamine sensitive even when themore resistant to histamine sensitization after number of cells administered is increased to toxicB. pertussis than 4 to 6 week old mice of the levels. (38). Maitland et al. (30) found that vari-same strain. Maitland et al. (30) mentioned the ous B. pertussis vaccines differed markedly infact that, with the strain of mice used in their their ability to sensitize mice to histamine. Theexperiments, there was no difference in sensitiza- vaccines tested by the latter had previously beention between male mice weighing 14 to 16, 18 to used by the British Medical Research Council in22, and 25 to 28 g at the time of vaccination. As extensive field trials and a description of theira general rule it would seem prudent to use mice preparation has been published (42). These vac-weighing 14 g or over to insure maximum sen- cines differ so much with respect to the strain ofsitization. organism, medium for growth, and killing agent

B. Sex of mice. Pittman (39) reported that employed that it is difficult to ascribe variationfemale mice were more susceptible to histamine in sensitizing potency to any one of these factors.than males. The difference between the LDso for However, Maitland et al. (30) stated that subse-the two sexes was greater (86 per cent) for per- quent experiments indicated that the sensitizingtussis-inoculated than for uninoculated animals ability of B. pertussis can be influenced by the(17 per cent). Maitland et al. (30) mentioned strain, the medium on which it is grown, and thesimilar findings; however, the differences between method of killing it. The latter have also charac-the sexes were somewhat smaller than those re- terized the histamine-sensitizing factor (HSF)corded by Pittman. Fink and Rothlauf (40) found (30). HSF was found in B. pertussis but not inno statistical difference in the reaction of unin- B. parapertussis; it was inactivated at 80 C in Ifoculated male and female mice to histamine. hr but only slightly affected by heating at 70 CHowever, the latter challenged their animals in- for 1 hr; it was antigenic and neutralized by anti-travenously whereas Pittman and Maitland et al. serum; it was destroyed when bacteria wereused the intraperitoneal route. Following Pitt- disintegrated by shaking with glass beads or by


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19581 RESPONSE OF MICE TO B. PERTUSSIS VACCINE 175

grinding after being freeze-dried. On the basis of greater numbers to lower doses (0.5 to 2 mg perthese properties, Maitland et al. differentiated mouse) (almost an LD1o) than to higher dosesHSF from other components of B. pertussis, (4 to 8 mg per mouse) of this drug. This peculiarnamely heat labile and heat stable toxin, hemag- type of response was also demonstrated in miceglutinin, capsular material, and agglutinogen. made histamine sensitive by adrenalectomy, butKind (16) reported that heating at 80 C for 30 did not occur in normal histamine-resistantmin reduced the histamine-sensitizing property animals. Ambrus et al. (48) showed that theand destroyed the anaphylactic- and pertussis- greater the natural resistance of a strain of micesensitizing properties of B. pertussis. However, to histamine, the less was the protection affordedtemperatures of 80 or 100 C failed to destroy the by an antihistamine. When the histamine sensi-ability of pertussis vaccine to kill mice previously tivity of mice is increased by adrenalectomy orsensitized with unheated vaccine. It was sug- pertussis inoculation, the protective effect of anti-gested that the sensitivity of pertussis-inoculated histamines is excellent (31, 49). These findingsmice to subsequent injections of pertussis is an suggest that the toxicity of histamine in pertussis-example of sensitivity to an endotoxin-like ma- inoculated histamine-sensitive mice and interial rather than an example of an antigen- histamine-resistant animals may be manifestedantibody reaction. through two different mechanisms (48).The relationship between the histamine-sensi-

tizing factor and the immunizing antigen of B. III. SENSITITY TO SEROTONINpertussis has not been completely clarified. Interest in the altered reactivity of pertussis-Pittman (43) demonstrated that good sensitizing inoculated mice was recently enhanced by thevaccines afford good protection in mice whereas observations of Munoz and Greenwald (5),poor histamine-sensitizing vaccines have low im- Munoz (6), Kind (7), Pittman (8), and Kallosmunizing potency. However, a vaccine heated to and Kallos-Deffner (9) that B. pertussis also37 C for 30 days in the presence of phenol lost sensitizes these animals to the lethal effects ofits sensitizing ability to a greater extent than its 5-hydroxytryptamine (serotonin). Kind (7) foundprotective capacity. Maitland et al. (30) found that pertussis-inoculated male mice shown to bethat stroma protective antigen, a fraction of B. histamine sensitive were also 40 to 50 times morepertussis originally prepared by Pillemer et al. susceptible to intraperitoneal challenge doses of(44) afforded both good protection and good serotonin. Munoz and Greenwald (5) reportedhistamine sensitization. It is likely that further that female mice of both histamine-sensitive andclarification of the relationship of the various histamine-resistant strains became 20 to 30 timescomponents of B. pertuwsis will come from the use more susceptible to intravenous doses of sero-of procedures recently employed by Schuchardt tonin after the administration of pertussis vac-et al. (45). These investigators have tested the cine. Serotonin sensitivity appeared on the firstbiologic activity of antigenic fractions of B. day, reached a peak about the third to fourthpertussis shown to be immunologically homogene- day and disappeared by the twenty-fifth dayous by serum diffusion techniques. By these after the administration of B. pertussis. Salmo-methods they have thus far demonstrated that nella typhosa and Erysipelothrix insidiosa, how-agglutinogen is a specific substance distinct from ever, failed to alter the susceptibility of mice tothe substance(s) responsible for protection, this drug (6).histamine sensitization, toxicity, and hemagglu- The concomitant sensitivity of the pertussis-tination. inoculated mouse to serotonin, histamine, and

B. Unusual Dose-Response Curve of Histamine anaphylaxis suggests that serotonin plays a roleB.UnusualDoseResspnonseCurveofH n in anaphylactic reactions of this species. The

Pertussis-Inoculated Mice following observations tend to support this view:Although the effect of histamine in mice can (a) lethal doses of serotonin in the mouse produce

be quantitated by rectal temperature measure- symptoms similar to those observed during ana-ments (46), most investigators have used death phylaxis (6); (b) the serotonin antagonistsas the end point. Munoz et al. made the interest- lysergic acid diethylamide (LSD) and reserpineing observation (47) that pertussis-inoculated inhibit the in vitro contraction of the sensitizedmice challenged with histamine succumb in mouse uterus upon addition of specific antigen


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(50); and (c) mouse lung not only has a relatively the horse serum was given subcutaneously andhigh concentration of serotonin but also contains the pertussis vaccine was administered intra-the enzymes which produce and destroy this abdominally; if the routes were reversed, how-amine (51). However, Munoz (6) has pointed out ever, no sensitization occurred (52). Likewise, ifthat LSD and reserpine are not specific anti- the pertussis vaccine and horse serum were in-serotonin drugs; in addition he was unable to jected 4 days apart the mice did not becomeprotect mice from anaphylactic death with these susceptible to subsequent inoculations of horsematerials. serum. Malkiel et al. (52) also performed experi-

ments to determine whether pertussis vaccinesensitized mice to active anaphylaxis by acting as

A. Passive Anaphylaxis an adjuvant. Crystalline egg albumin (Ea)

The original observation that pertussis-inocu- mixed with pertussis vaccine was injected intra-lated mice became histamine sensitive (4) led to abdominally into mice. A large percentage of theexperiments which tested the susceptibility of animals subsequently succumbed to challengethese animals to anaphylactic shock. Kind (10, doses of the homologous antigen. However, nei-11) reported that mice injected with B. pertu88is ther precipitating, nonprecipitating, nor uni-vaccine possessed an enhanced sensitivity to the valent antibodies were found in mouse anti-Ealethal effects of passive anaphylaxis induced by serum. Recently, Kind (53) showed that pertussisthe intravenous injection of antiserum and anti- vaccine administered to mice along with chickengen in rapid succession. Similar results were red blood cells (CRBC) enhanced the productionobtained by others (13, 14). Pittman (14) demon- of agglutinins to CRBC and also induced ana-

strated that anaphylaxis occurred when an anti- phylactic sensitivity to subsequent challengeserum was administered either 48, 24, or 6 hr doses of CRBC. The ability of B. pertussis tobefore the antigen; Munoz et al. (13) stated that stimulate the formation of agglutinins seemed tothe optimal time for challenge was 4 to 6 hr after bear no relationship to its anaphylaxis-sensitizingthe administration of antiserum. Both groups of effect. However, it is conceivable that pertussisinvestigators injected the antiserum 5 days after vaccine may have augmented the manufacturethe mice were inoculated with B. pertussis of some type of sensitizing antibody which couldvaccine (at which time the animals were maxi- not be measured by the methods employed.mally histamine sensitive) and Munoz et al. noted Greenberg and Fleming (54) had previously re-

that it was difficult to produce sensitization after ported that pertussis vaccine enhanced thethe tenth day. Pittman (14) found that 4 to 8 immunizing efficiency of diphtheria toxoid inmg per kg of antibody nitrogen would sensitize guinea pigs (as measured by a change in the50 per cent of the pertussis-inoculated mice and Schick test from positive to negative). TheMunoz et al. (13) reported that 187 jug of antibody mechanism of the adjuvant effect of B. pertussisnitrogen (9.3 mg per kg per 20 g mouse) produced is unknown. However, it is of interest to noteconsistent sensitization. Recently, Munoz et al. that Parfentjev and Manuelidis (55) found that(15) have presented a detailed analysis of opti- mice injected with pertussis vaccine developedmal conditions for the production of passive an increase in splenic weight as well as a lympho-anaphylaxis in pertussis-injected mice. cytosis. Fichtelius and Hassler (56) inoculated

adrenalectomized rats for 14 days with repeatedB. Active Anaphylaxis injections of pertussis vaccine. At the end of this

Malkiel and Hargis (12) demonstrated that period the formation of lymphocytes in thymuspertussis vaccine administered along with an and lymph nodes was investigated with the aidantigen (horse serum) sensitized mice to subse- of p32. Compared with adrenalectomized controls,quent injections of that antigen. Of 102 mice the formation of lymphocytes was clearly in-injected intraperitoneally with pertussis vaccine creased in the pertussis animals.and horse serum, 95 succumbed to challenge The concomitant sensitivity of the pertussis-doses of horse serum administered 15 days later. inoculated mouse to serotonin, histamine, andIn contrast, the shocking dose of horse serum anaphylaxis can hardly be considered coinci-killed only 3 of 66 mice previously sensitized with dental. It is tempting to postulate that enhancedhorse serum alone. Sensitization was induced if susceptibility to active and passive anaphylaxis


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can be explained on the basis of the concurrent by measurements of rectal temperature dropssensitivity to histamine and serotonin. Active (61, 62) and by hematocrit changes (63). Theanaphylaxis, however, will occur in pertussis- shock organ in the mouse has not been deter-inoculated mice at a time when histamine and mined, although emboli have been observed inserotonin sensitivity have declined greatly or the blood vessels of the lung shortly after thehave completely disappeared (13). Persistence of administration of challenge doses of antigen (64).anaphylactic sensitivity in the absence of sero- Recent experiments implicating serotonin intonin and histamine susceptibility (e.g., 40 days mouse anaphylaxis (5-7) suggest that the afore-after pertussis and antigen inoculation) can per- mentioned pulmonary emboli may have beenhaps be attributed to the adjuvant properties of aggregates of platelets.B. pertussis (53). Sufficient antibody may be Although pertussis vaccine increases the sus-available at this time to cause the release of ceptibility of mice to anaphylactic shock itamounts of histamine and serotonin large enough should be noted that it does not enhance Arthusto be lethal to animals no longer sensitive to sensitivity in these animals (65) nor does itthese materials. It has been demonstrated that intensify the reaction of the sensitized mousethe use of Freund's adjuvant along with the uterus to challenge doses of the homologoussensitizing antigen in mice results in a heightened antigen (50). The anaphylaxis sensitizing factormortality rate upon subsequent injection of the of B. pertussis was destroyed by heating thehomologous antigen (57). Although the adjuvant vaccine at 80 C for 30 min (16) and variouseffect of B. pertussis may provide an explanation fractions of B. pertussis were found to possessfor the increased susceptibility of mice to active this factor (52).anaphylaxis in the absence of histamine or sero-tonin sensitivity, the proponents of a major role v. PERTUSSIS VACCINE AND THE ADRENAL GLANDof histamine and serotonin in mouse anaphylaxis Observations that both adrenalectomized andmay find it more difficult to account for the oc- pertussis-inoculated mice were more susceptiblecurrence of enhanced sensitivity to passive ana- to the lethal effects of histamine and anaphylaxisphylaxis in the absence of histamine or serotonin than normal controls suggested that pertussissensitivity. Munoz et at. (15) have recently vaccine exerted its effect through injury of thereported that CF1 mice, which do not become adrenal gland (11). This supposition was sup-histamine sensitive after pertussis vaccination, do ported by the fact that cortisone protected micebecome sensitive to passive anaphylaxis. In addi-tion, they demonstrated that another strain of the fatal effects of histamie (66, 67) andmice became sensitive to both histamine and Gadsden (69), Chedo d (22), and Malkiel (70)passive anaphylaxis 5 days after pertussis inocu- Gase 6) hdd(2,adMlil(0latsioean;however, 7 dayslater, theanimals were- presented evidence of normal adrenal function inlation;however7 days later, theanimalswerepertussis-inoculated mice and the latter (70) alsostill sensitive to histamine but were no longer reported the absence of histological changes insusceptible to passive anaphylaxis. Munoz et al. the adrenal glands of such animals. Gauthier e

(15) have stated that, just as in the case of hyper- al. (71) found a strain of mice which becamesensitivity to histamine, active anaphylaxis can histamine sensitive after inoculation with per-be produced at a time when serotonin hyper- tussis vaccine but not after adrenalectomy. Itsensitivity has disappeared, and that the in thus seems likely that the histamine sensitivitycreased sensitivity to passive anaphylaxis disap- induced bypertussis vaccine is not due to anypears at a time when serotonm sensitivity is still harmful effect of B. pertussis on the adrenals.present. It should be noted that mast cells con- The protective effect of cortisone in histaminetain both serotonin and histamine and that shock and anaphylaxis may well be pharmacologi-locally injected antigen initiates a more wide- cal in nature rather than a form of replacementspread degranulation of local tissue mast cells in therapy (71). In a recent paper, Munoz et al. (15)sensitized mice than in controls (58). have suggested that B. pertussis may act at a

Other conditions which sensitize mice to ana- level beyond the adrenal glands by either inter-phylaxis are adrenalectomy (59) and ionizing fering with the utilization of steroids, enhancingradiation (60, 61). Sublethal anaphylaxis in the their destruction, or increasing the tissue require-pertussis-inoculated mouse has been quantitated ments for these compounds.


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VI. ADDITIONAL BIOLOGICAL EFFECTS OF infection with organisms whose virulence may toB. PBRTUSSIS some extent be due to their endotoxin content.

Although B. pertussi.is unique in sensitizing Whether pertussis inoculation will result inmicetohisee

enhanced resistance or enhanced susceptibilitywill thus likely depend upon such factors as

it shares with other gram-negative organisms m the dose of pertussis vaccine administered andthe ability to alter the susceptibility of mice to the nature, virulence, and route of inoculation ofbacterial infections. Landy (72) reported thatlipopolysaccharides extracted from various bac- infecting o asm.(including~~~~~~B. pets.)iceaeh eit Andersen (73) has confirmed the observationsteria (including B. pertussi increased the resist-of Evans and Perkins (74) that pertussis vaccineance of mice challenged 24 hr later with Salmo-nella typhosa and also caused an elevation in gvnsmlaeul inrcrbal)wt hproperdintiterofn50apercausentor mrevabiovi challenge dose of B. pertussis was able to protectproperdin titer of 50 per cent or more abovenormal. Dubos and Schaedler (3) found that mice against death. The protective effect of pertussis

vaccine was shown to have both nonspecific andinoculated with B. pertussis or Kiebsila pneu-moniae possessed an increased susceptibility t specific components. Andersen reported (75) that

viruletstaphylococci when infected a few hours pertussis vaccine caused a decrease in resistancevirulent ~~~~~~~~toheterologous infection during the first 2 weeks

after the administration of the vaccine. In con-t

trast, mice infected a few days after vaccination and an increased resistance 20 to 30 days after

d a infection. The latter also found (76) that intra-developed an increased resistance to the chal-naa inclto fB etmsi iepoue

lenge doses of staphylococci. Dubos and Schaedler nasal ioculation of B. pertussis in mice produced

(3) likewise presented excellent arguments against ploayeeaadta trl xrcsfo*3ewiepreenteexcellen argumes a t virulent strains had the same effect. Pittman (77)the role of properdin in the nonspecific resistance had previously demonstrated that respiratoryof mice to bacterial infections, infection with B. pertussis sensitized mice toAlthough B. pertussis as well as other organisms histamine and that the development of histamine

may induce an enhanced resistance of mice to . . .bacterial infections, B. pertussis also has the sestvt.a.creae ih h rsneobacterialinfectiofs,loweringthsistancehaso lung lesions. The ability of pertussis vaccine tounique property of lowering the resistance of mice induce so many biological changes in the mouseto living heterologous organisms (at a time when not only explains difficulties in obtaining repro-elevated properdin titers would be expected). ducible results in mouse protection tests with B.Parfentjev et al. reported that B. pertussis mi- .creased the susceptibility of mice to challenge pertussisnbutealsoeindicatesnthe ncessidoses of Proteus vulgaris (18), Pasteurella multo-cida (18), and Pseudomonas fluorescens (20) (at a VII. HYPOTHESEStime when Dubos and Schaedler (3) demonstratedincreased heterologous resistance). The author Since pertussis-inoculated mice possess an(unpublished observations) has recently found enhanced sensitivity to the lethal effects ofthat, 13 days after pertussis inoculation, mice histamine and serotonin it is tempting to postu-possessed an enhanced susceptibility to the lethal late that the increased susceptibility of theseeffects of Escherichia coli endotoxin as well as to animals to anaphylaxis, peptone, endotoxins, etc.,the intraperitoneal injection of 2.3 X 106 living is owing to the release of histamine and serotoninE. coli organisms. The large number of organisms by these agents and conditions. Experimentsneeded to produce a fatal outcome (as was the designed to test this hypothesis have been difficultcase in some of the aforementioned experiments to evaluate. Thus, Hunder and Spink (27) foundof Parfentjev et al.), as well as the concomitant that mice inoculated with pertussis vaccine weresensitivity to endotoxin, suggest that the cause sensitized to the lethal effects of histamine andof death was endotoxic in nature. peptone. Such animals could be protected from

B. pertussis is a complex organism. It contains, peptone shock with an antihistamine. Paradoxi-among many other components, a lipopolysac- cally, however, a strain of mice which does notcharide which may cause an enhanced heterolo- become histamine sensitive after pertussis inocu-gous resistance to bacterial infection; it likewise lation also developed a susceptibility to the lethalpossesses a factor which sensitizes mice to endo- effects of peptone. The failure of antihistaminestoxin, thus causing an increased susceptibility to to protect pertussis-inoculated mice from endo-


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toxic death has been attributed to the possible VIII. REFERENCESinability of antihistamines to reach the site of 1. RowiLy, D. 1955 Stimulation of naturalaction of endogenously released histamine (23). immunity to Escherichia coli infection.On the other hand, interpretations based on Lancet, 268, 232-234.positive protective effects of antihistamines and 2. LANDY, M. 1956 Increased resistance to in-antiserotonin drugs have been questioned on the fection developed rapidly after adminis-basis of a presumed lack of specificity of these tration of bacterial lipopolysaccharides.agents (6, 60). Experimental data listing sero- Federation Proc., 15, 598.tonin and histne values in the organs, blood, 3. DuBos, R. J., AND SCHAEDLER, R. W. 1956and plasma of pertussis-inoculated mice during Reversible changes in the susceptiblity ofanaphylactic, peptone, and endotoxic shock mice to bacterial infections. J. Exptl.w yldbe mostl valuable.

and enclotonc Knock Med., 104, 53-65.would be most valuable. 4. PARFENTJEV, I. A., AND GooDUNE, M. A.The manner in which pertussis vaccine alters 1948 Histamine shock in mice sensitized

the mouse so that it becomes so highly sensitive with Hemophilus pertussis vaccine. J.to histamine and serotonin has not yet been Pharmacol. Exptl. Therap., 92, 411-413.determined. It may be that B. pertussis interferes 5. MUNOZ, J., AND GREENWALD, M. A. 1957with the destruction of these amines by inhibition Effect of H. pertusi8 on sensitivity of miceof monoamine and diamine oxidase. Kind and to serotonin. Federation Proc., 427.Woods (78) reported that the lungs of pertussis- 6 MUNOZ, J. 1957 Effect of H. pertussi8 oninoculated mice had a reduced hins sensitivity of mice to serotonin. Proc.activity; however, these findings could not be Soc. Exptl. Biol. Med., 95, 328-31.reprduc byhowever athese insubsequldenotbexpe 7. KIND, L. S. 1957 Sensitivity of pertussis-reproduced by the authors m subsequent exper-t inoculated mice to serotonin. Proc. Soc.ments. Angelakos and Loew (79) were unable to Exptl. Biol. Med., 95, 200-201.increase the histamine toxicity in mice and rats 8. PI"riMN, M. 1957 Effect of Hemophilusfollowing treatment with histaminase inhibitors pertussis on immunological and physiologi-(with the possible exception of imidazole). Fishel cal reactions. Federation Proc., 16, 867-(80) could not correlate the decreased resistance 872.of the pertussis-injected mouse to histamine with 9. KALLOS, P., AND KALLOB-DEFFNER, L. 1957specific alteration in the free amino acid concen- Effect of inoculation with H. pertussis vac-tration of various tissues. Likewise no increase in cine on susceptibility of albino mice to 5-the histamine content of tissues could be found hydroxytryptamine (serotonin). Intern.following.ertusinoculoun.

. Arch. Allergy Appl. Immunol., 11, 237-245.following pertussis inoculation. 10. KIND, L. S. 1951 The altered reactivity ofPresent investigations of the unique sensitizing mice after immunization with Hemophilus

properties of B. pertussis are likely based on the pertussi8 vaccine. Ph. D. Thesis, Yaletwo following assumptions: (a) sensitivity to University.histamine, serotonin, anaphylaxis, endotoxins, 11. KIND, L. S. 1953 The altered reactivity ofetc., is due to a defect in steroid metabolism and mice after immunization with Hemophilusincreasedsusptibtytotelehalffecspertussis vaccine. J. Immunol., 70, 411-420.(b)ienreased susceptiblaty to the lethal effects of 12. MALKIEL, S., AND HARGIS, B. J. 1952 Ana-

endotoxins, anaphylaxis, peptones, etc., is due to phylactic shock in the pertussis vaccinatedthe release of histamine and/or serotonin in an mouse. Proc. Soc. Exptl. Biol. Med., 80,animal somehow made sensitive to histamine and 122.serotonin. The first proposition would seem to be 13. MUNOZ, J., SCHUCHARDT, L. F., AND VERWEY,amenable to proof or disproof in the near future. W. F. 1954 Passive anaphylaxis in H.Thesnsipertussie treated mice. Federation Proc.,The second assumption is probably an over- 13, 507.

simplification and its clarification will depend 14. PITTMAN, M., AND GERMuTH, F. G., JR. 1954upon a better understanding of the complex Some quantitative aspects of passive ana-interrelationships between histamine, serotonin, phylaxis in pertussis-vaccinated mice. Proc.epinephrine, and acetylcholine. In this connec- Soc. Exptl. Biol. Med., 87, 425-428.tion, studies of mast cells (which contain both 15. MUNOZ, J., SCHUC:ARDT,L. F., AND VERWEY,

W. F. 1958 Anaphylaxis in Hemophilusserotoin and histamie) wil certainly bear pertussis-treated mice. J. Immunol., 80,watching. 77-84.


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16. KIND, L. S. 1956 Effects of heat on the 29. KIND, L. S. 1955 Effect of the histaminesensitizing and shocking properties of liberator 48/80 in histamine-sensitive mice.Hemophilus pertussz8. J. Immunol., 77, J. Allergy, 26, 507-508.115-116. 30. MAITLAND, H. G., KOHN, R., AND MACDON-

17. PARFENTJEV, I. A., GOODLINE, M. A., AND ALD, A. D. 1955 The histamine sensitiz-VIRION,M. E. 1947 A study of sensitivity ing property of Hemophilu8 pertUSSi8. J.to Hemophilus pertu88is in laboratory ani- Hyg., 53, 196-211.mals. J. Bacteriol., 58, 603-611. 31. MALKIEL, S., AND HARGIS, B. J. 1952 Ana-

18. PARFENTJEV, I. A. 1953 Effect of hyper- phylactic shock in the pertussis-vaccinatedsensitivity on susceptibility to infection. mouse. J. Allergy, 23, 352-358.Intern. Congr. Microbiol., 6th Congr. 32. MALKIEL, S., AND HARGIS, B. J. 1952 Hista-Rome, 3, 38. mine sensitivity and anaphylaxis in the

19. PARFENTJEV, I. A. 1955 Bacterial allergy pertussis-vaccinated rat. Proc. Soc. Exptl.increases susceptibility to influenza virus Biol. Med., 81, 689-691.in mice. Proc. Soc. Exptl. Biol. Med., 90, 33. PITTMAN, M., AND GERMUTH, F. G. 1954373-375. Some quantitative aspects of passive

20. ARcH, R. N. AND PARFENT.TEV, I. A. 1957 anaphylaxis in pertussis-vaccinated mice.The effect of Hemophilus pertussi8 sensiti- Proc. Soc. Exptl. Biol. Med., 87, 425-428.zation on the increase of susceptibility of 34. HALPERN, B. N., AND WOOD, D. R. 1950mice to infection by a saprophyte. J. The action of Promethazine (phenergan)Infectious Diseases, 101, 31-34. in protecting mice against death due to

21. PARFENTJEV, I. A. 1954 Increased suscepti- histamine. Brit. J. Pharmacol., 5, 510-516.bility to shigella endotoxin and to hista- 35. MUNOZ, J., AND SCHUCHARDT, L. F. 1954mine after immunization to H. pertus8is. Sensitivity to histamine of adrenalectomizedYale J. Biol. Med., 27, 46-50. mice from different strains. J. Allergy, 25,

22. CHEDID, L. 1954 Disparition de I'action 125-129.antiendotoxique de la cortisone chez la 36. PARFENTJEV, I. A. 1955 Anaphylaxis andsouris immunis6e par le bacille de Bordet- histamine shock in mice. Proc. Soc. Exptl.Gengou. Ann. Endocrinol. Paris, 15, 746- Biol. Med., 89, 297-299.750. 37. PARFENTJEV, I. A. 1955 A hypersensitivity

23. ABERNATHY, R. S., AND SPINK, W. W. 1956 phenomenon in animals bearing tumors.Studies on the role of histamine in the in- Proc. Am. Assoc. Cancer Research, 2, 38-creased susceptibility to bacterial endo- 39.toxins induced by pertussis vaccine. J. 38. MUNOZ, J., AND SCHUCHARDT, L. F. 1953Immunol., 77, 418-422. Studies on the sensitivity of mice to hista-

24. ROWEN, M., Moos, W. W., AND SAMTR, M. mine following injection of Hemophilus1955 Increased radiation sensitivity of pertussis. J. Allergy, 24, 330-334.pertussis-vaccinated mice. Proc. Soc. 39. PITTMAN, M. 1951 Influence of sex of miceExptl. Biol. Med., 88, 548-50. on histamine sensitivity and protection

25. KIND, L. S., AND GADSDEN, R. H. 1953 Ad- against Hemophilu8 pertussis. J. Infectiousrenal function tests in mice sensitized to Diseases, 89, 296-299.histamine with Hemophilus pertussis vac- 40. FINK, M. A., AND ROTHLAUF, M. V. 1954cine. Proc. Soc. Exptl. Biol. Med., 84, Variations in sensitivity to anaphylaxis and373-375. to histamine in inbred strains of mice.

26. MUNOZ, J., AND SCHUCHARDT, L. F. 1957 Proc. Soc. Exptl. Biol. Med., 85, 336-338.Effect of H. pertussi8 on sensitivity of mice 41. HALPERN, B. N., AND Roux, J. 1949 Inter-to cold stress. Proc. Soc. Exptl. Biol. Med., ference entre l'immunisation par l'Hemo-94, 186-190. philus pertussis et l'intoxication hista-

27. HUNDER, G., AND SPINE, W. W. 1957 Pro- minique. Comp. rend. soc. biol., 143,duction of peptone shock in mice following 923-927.administration of H. pertusis vaccine. 42. Medical Research Council 1956 VaccinationProc. Soc. Exptl. Biol. Med., 95, 55-57. against whooping-cough. British Med. J.,

28. LOEW, E. R., AND WOODMAN, E. 1956 Fail- 2, 454-462.ure of pertussis vaccine and adrenalectomy 43. PITTMAN, M. 1951 Comparison of hista-to sensitize mice to lethal action of epi- mine-sensitizing property with the protec-nephrine, methacholine and acute heat tive activity of pertussis vaccine for mice.stress. Am. J. Physiol., 187, 615. J. Infectious Diseases, 89, 300-304.


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44. PILLEMER, L., BLUIM, L., AND LEPOW, I. N. anaphylaxis in albino mice with the aid of1954 Protective antigen of Hemophilus adjuvants. J. Lmmunol., 65, 687-700.pertussis. Lancet, 1, 1257-1260. 58. CARTER, P. B., HIGGINBOTHAm, R. D., AND

45. SCHUCHARDT, L. F., SAGIN, F. F., AND MUNOZ, DOUGHERTY, T. 1957 The local responseJ. 1957 Relationship of agglutinogen to of tissue mast cells to antigen in sensitizedother antigens of H. pertuesis. Federation mice. J. Immunol., 79, 259-263.Proc., 16, 432. 59. WEISER, R. S., GOLUB, 0. J., AND HABE,

46. KIND, L. S. 1954 Antagonism of cortisone D. M. 1941 Studies on anaphylaxis into body temperature reducing effect of the mouse. J. Infectious Diseases, 68,histamine. Proc. Soc. Exptl. Biol. Med., 97-112.85, 371-4372. 60. STONER, R. D., AND HALE, W. M. 1954

47. MUNOZ, J., SCHUCHARDT, L. F., AND VERWEY, Increased susceptibility of mice to ana-W. F. 1954 Studies on the sensitivity of phylactic shock following cobalt-60 gammamice to histamine following injection of radiation. J. Immunol., 72, 419-423.Hemophilus pertu88i8. J. Allergy, 25, 120- 61. MORGAN, P., SHERWOOD, N. P., WERDER,124. A. A., AND YOUNGSTROM, K. 1957 Effect

48. AMBRUB, J. L., GUTH, D. S., GOLDSTEIN, S., of ionizing radiation of anaphylactic shockGOLDBERG, M. E., AND HARRISON, J. W. E. in the mouse. Air Force School of Aviation1955 Toxicity of histamine and antagonism Med., Project No. 57-34, 1-18.between histamine and antihistamines in 62. KIND, L. S. 1955 Fall in rectal temperaturevarious strains of mice. Proc. Soc. Exptl. as an indication of anaphylactic shock inBiol. Med., 88, 457-459. the mouse. J. Immunol., 74, 387-390.

49. HALPERN, B. N., AND WOOD, D. R. 1950 63. FULTON, J. D., HARRIS, W. E., AND CRAFT,The action of promethazine in protecting C. E. 1957 Hematocrit change as anmice against death due to histamine. Brit. indication of anaphylactic shock in theJ. Pharmacol., 5, 510-516. mouse. Air Force School of Aviation

50. FINK, M. A., AND RoTHLAUF, M. V. 1955 Med., Project No. 57-75, 1-7.In vitro anaphylaxis in the sensitized mouse 64. KIND, L. S., AND GALLEMORE, J. I. 1956uterus. Proc. Soc. Exptl. Biol. Med., 90, Pulmonary vascular changes in the mouse447-480. during anaphylactic shock. Proc. Soc.

51. WEISSBACH, H., WAALKE5, T. P., AND UDEN- Exptl. Biol. Med., 92, 345-347.FRIEND, S. 1957 Presence of serotonin in 65. BENEDICT, A. A., AND TIPs, R. L. 1954lung and its implication in the anaphylactic Actively and passively induced Arthusreaction. Science, 125, 235-236. reactions in the mouse. Proc. Soc. Exptl.

52. MALKIEL, S., HARGIS, B. J., AND FEINBERG, Biol. Med., 87, 618-622.S. M. 1953 Anaphylactic shock in the 66. KIND, L. S. 1953 Inhibition of histaminemouse inoculated with Hemophilus pertussis. death in pertussis-inoculated mice by corti-J. Tmmunol., 71, 311-318. sone and neoantergan. J. Allergy, 24, 52-

53. KIND, L. S. 1957 Relationship of the ana- 59.phylaxis sensitizing and adjuvant properties 67. HALPERN, B. N., BENACERRAF, B., AND BRIOT,of Hemophilus pertussis vaccine. J. Im- M. 1952 Roles of cortisone, desoxycorti-munol., 79, 238-242. costerone and adrenaline in protecting

54. GREENBERG, L., AND FLEMING, D. S. 1948 adrenalectomized animals against hemor-The immunizing efficiency of diphtheria rhagic, traumatic and histamine shock.toxoid when combined with various anti- Brit. J. Pharmacol., 7, 287-297.gens. Can. J. Public Health, 39, 131-135. 68. NELSON, C. T., Fox, C. L., AND FREEMAN,

55. PARFENTJEV, I. A., AND MANUELIDIS, E. E. E. B. 1950 Inhibitory effect of cortisone1956 Hemopoietic response in mice in- on anaphylaxis in the mouse. Proc. Soc.jected with pertussis vaccine. Federation Exptl. Biol. Med., 75, 181-183.Proc., 15, 607. 69. KIND, L. S., AND GADSDEN, R. H. 1953

56. FIciITEuus, K. E., AND HASSLER, 0. 1958 Adrenal function tests in mice sensitized toInfluence of pertussis vaccine on the lym- histamine with Hemophilus pertussis vac-phocyte production in adrenalectomized cine. Proc. Soc. Exptl. Biol. Med., 83,rats. Acta Pathol. Microbiol. Scand., 42, 373-375.189-192. 70. MALKIEL, S. 1956 Anaphylactic shock in

57. WHEELER, A. H., BRANDON, E. M., AND the mouse vaccinated with HemophilusPETRENCO, H. 1950 The enhancement of pertussis. J. Allergy, 27, 445-449.


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71. GAUTHIER, G. F., LoEw, E. R., AND JENKINS, to heterologous infection. Acta Pathol.H. J. 1955 Histamine sensitivity of ad- Microbiol. Scand., 40, 235-247.renalectomized and pertussis treated mice. 76. ANDERSEN, E. K. 1957 Studies on the oc-

Proc. Soc. Exptl. Biol. Med., 90, 726728. currence of lung oedema in mice after intra-

72. LANDY, M. 1956 Increase in resistance fol- nasal H. pertussis inoculation. Acta

lowing administration of bacterial lipo- Pathol. Microbiol. Scand., 40, 248-266.

polysaccharides. Ann. N. Y. Acad. Sci., 77. PITTMAN, M. 1951 Sensitivity of mice to

66, 292-303. histamine during respiratory infection by

73. ANDERSEN, E. K. 1957 Demonstration of Hemophilue pertusee8. Proc. Soc. Exptl.

proimmunity in the early immunity of 78 IND L. S. AND WOODS, E. F. 1954 Inacti-pertussis vaccinated mice. Acta Pathol. vation of histamine by lung tissue from

Microbiol. Scand., 40, 227-234. histamine sensitive and histamine resistant

74. EVANS, 0. G., AND PERKINS, F. T. 1954 In- mice. Proc. Soc. Exptl. Biol. Med., 84,terference immunity produced by pertussis 601-603vaccine to pertussis infection in mice. Brit. 79. ANGELAKOS, E. T., AND LOEW, E. R. 1957J. Exptl. Pathol., 35, 603-608. Histamine toxicity in mice and rats follow-

75. ANDERSEN, E. K. 1957 Studies on repro- ing treatment with histaminase inhibitors.ducibility in detecting a decline in protec- J. Pharmacol. Exptl. Therap., 119, 444-451.tion during immunization against H. per- 80. FISHEL, C. W. 1957 Host parasite relation-tussis infection, and on the effect of pertus- ship in experimental pertussis. J. Infec-sis immunization on the resistance of mice tious Diseases, 101, 20-30.


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thealtered reactivity of mice after inoculation with ... · rine (28), acute heat stress (28),...

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