Bernard B. Levine

Prediction of penicillin allergy by immunological tests

Abstract This paper serves to evaluate objective immunological tests to predict penicillin allergy. Prospective immediate skin and serum tests were performed on a total of 218 patients with past histories of penicillin allergy who had major medical indication for penicillin and who were then treated with penicillin depending upon the test results. Skin tests were found to be valuable predictive tests for immediate (including anaphylactic) and accelerated urticarial allergic reactions to penicillin. The clinical value of these tests is discussed, as well as the possible meaning of the data obtained with regard to the immune mechanisms of various allergic reactions to penicillin.

Specific in vitro histamine release from basophils by bivalent haptens: Evidence for activation by simple bridging of membrane bound antibody

Abstract Rabbits were immunized with either BPO or DNP protein conjugates to produce reaginic antibody. Leukocytes from animals were tested for histamine release with monovalent, bivalent and mixed haptens. Monovalent haptens were incapable of releasing histamine whereas all the bivalent compounds were active. Leukocytes from rabbits immunized with both BPO and DNP conjugated proteins were capable of releasing histamine with a mixed hapten with the formula BPO-NH-(CH2)6-NH-DNP. The mixed hapten was inactive in rabbits immunized with either hapten alone. It was also negative with cells, from singly immunized animals (BPO or DNP) mixed in vitro. A homologous series of bivalent BPO haptens were tested for their ability to release histamine from cells of BPO-immunized rabbits. The general formula of these compounds was BPO-NH-(CH2)n-NH-BPO. Short chain compounds where n = 3 were active in releasing histamine but were less active than compounds groups were separated by rigid diphenyl bridges the longer chain compounds were equally active. The bivalent haptens were as active on a molar basis as a multivalent compound. This indicates that the hapten binding sites on some of the IgE molecules must be very shallow. The results are interpreted to indicate that activation of a basophil is due to bridging of two molecules on the cell surface with the resultant formation of a dimer. The evidence suggests that bridging does not occur withn the two Fab portions of a single IgE molecule.

Immune responses of inbred mice to repeated low doses of antigen, relationship to histocompatibility (h-2) type.

Immunization of inbred strains of mice with repeated minute doses (0.1 to 1.0 microgram) of hapten-protein conjugates demonstrated wide differences in the magnitude of their antibody responses, which were related to the histocompatibility (H-2) type of the strains. Immunization with a single high dose (100 micrograms) of antigen failed to demonstrate these differences.

Allergy to human seminal plasma.

THE infrequency of the syndrome of allergy to human ejaculate1 prompts us to report another such case. In addition, we present immunologic data including histamine release, and the finding that the...

The nature of the antigen-antibody complexes initiating the specific wheal-and-flare reaction in sensitized man

To study the nature of the antigen-antibody complexes which initiate the specific wheal-and-flare (W & F) reaction in sensitized man, a homologous series of bivalent, oligovalent, and multivalent benzylpenicilloyl (BPO) haptens were quantitatively compared for their effectiveness in eliciting W & F in BPO-sensitized human subjects.A series of seven divalent haptens were capable of eliciting W & F, but these generally were not maximally effective elicitors. Of the divalent haptens, those with separation chains of 8 or 13 A were the most effective. Of the oligovalent haptens, maximal effectiveness was attained with BPO(6)-lysine(7), and not with BPO(2)-lysine(3) or BPO(4)-lysine(4), i.e., haptens which are 6- 3- and 4-valent, respectively, from a chemical point of view. However, evidence was obtained from quantitative precipitation experiments which indicated that BPO(6)-lysine(7) functions as a trivalent hapten immunologically, i.e., capable of binding three antibody molecules per mole hapten. Large molecularsized haptens with immunological valences of 7 or 12, but in which the haptenic groups were widely separated, were comparatively ineffective elicitors of W & F. In individual subjects, threshold W & F reactions were obtained with equimolar concentrations of the differently sized divalent, oligovalent, and multivalent haptens. The results demonstrate that for maximally effective elicitation of W & F by haptens, trivalency with optimal distances of separation of haptenic groups is necessary and sufficient. These results indicate the requirement for the formation of a high energy complex of two or three membrane-fixed skin-sensitizing antibody molecules closely bridged together by the elicitor hapten as the initiator of the W & F reaction.

Genetic Control in Guinea Pigs of Immune Response to Conjugates of Haptens and Poly-L-Lysine

Random-bred Hartley strain guinea pigs which do not respond immunologically to conjugates of hapten and poly-L-lysine mere mated with heterozygous guinea pigs which do. These responders were considered heterozygous for this trait since their mating resulted in at least one nonresponder offspring. Of 31 offspring from 10 breeding pairs (nonresponder x heterozygous responder) 14 were responders. There was no evidence that this trait is sex-linked. This finding confirms the view that, in guinea pigs, development of an immune response to the aforementioned conjugates is a genetically transmitted autosomal, unigenic Mendelian dominant trait.

Antigenic specificities of skin-sensitizing antibodies in sera from patients with immediate systemic allergic reactions to penicillin

Abstract The sera of five patients with recent immediate systemic allergic reactions to penicillin were tested by the passive transfer technique with penicillin G and with several multivalent haptenic conjugates and simple chemicals derived from penicillin. Four of the five sera reacted to crystalline penicillin G and not to any of the other test materials. The fifth serum reacted to the multivalent benzylpenicilloyl conjugates and not to any of the other test materials. These results indicate that, in order to detect the potential immediate systemic allergic reactor, patients should be skin-tested with both penicillin G and a benzylpenicilloyl-polylysine conjugate rather than with the latter material alone.

Effects of compounds which inhibit antigenic release of histamine and phagocytic release of lysosomal enzyme on glucose utilization by leukocytes in humans.

Summary Antigenic release of histamine from leukocytes of hypersensitive persons is not accompanied by release of the lysosomal enzyme, β-glucuronidase. Likewise, histamine is not released during phagocytic release of β-glucuronidase. Both processes are inhibited by dibutyryl cyclic 3′, 5′-adenosine monophosphate, theophylline, nicotinamide, and ethanol. These four compounds were found to also suppress utilization of glucose by leukocytes from humans, the concentrations and rank order of potency required being the same magnitude as inhibited release of histamine. Considerations pertinent to determination of mechanisms which could account for the effects of these compounds are discussed. The skillful and diligent technical assistance of Misses Janet Strollo, Bonnie Boilini and Kathryn Krakauer are gratefully acknowledged.

PREDICTION OF PENICILLIN ALLERGY BY IMMUNOLOGICAL TESTS

!L’his paper serves to evaluate objective immunological tests to predict penioillin allergy. Prospective immediate &in and serum tests were performed on a total of ,818 patients with past histories of penicillin allergy who had major medical in&ation for penicillin and who were then treated with penicillin depending qmn. the test results. Slcin tests were fownd to be valua&le predictive tests for immediate (in&ding anaphylaotio) and accelerated urtioarial allergic reactions to pentillin. !Che olinicd value of these tests is discu.ssed, as well as the possible meaning of the data obtained with regard to the immune mechanisms of zrc~iozls allergio reaotions to penicillin.

The Genetic Control of the Immune Response to Hapten-Poly-L Lysine Conjugates in Guinea Pigs

That the immune response to an immunogen by an individual animal is under genetic control is evident from the results of several studies. For example, Fjord-Scheibel (1943), Carlifanti (1948), and Sang and Sobey (1954) showed a statistically significant relationship between the abilities of parents and their offspring to produce high serum titers of antibody to a given immunogen. Also, Ibsen (1959) showed that inbred strains of mice required different doses of antigen to produce a standardized immune response. Recently, Sobey et al. (1966) observed genetically transmissable differences among random bred mice to respond immunologically to bovine serum albumin. Finally, Arquilla and Finn (1965), in studies of the immune response of inbred guinea pigs to bovine insulin, found that strain 2 guinea pigs could make antibodies to an antigenic determinant of insulin to which strain 13 could not make antibodies. However, breeding studies showed complex patterns of inheritance.