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Clinical Significance of Insulin Allergy and Insulin Resistance Studies: Application to Drug “Desensitization” Concept and Efficacy
AAAAI ABSTRACTS FROM YESTERYEAR WITH COMMENTARIES These abstracts from the 1969 and 1970 American Academy of Allergy, Asthma & Immunology meetings are presented with reflective commentaries by the original authors that highlight new developments or provide insights into the research presented in these abstracts from yesteryear.
IgE Associated with Reaginic Antibodies to Various Allergens Konrach Wicher, Ph.D., Koji Ito, M.D., Takeru Ishikawa, M.D., and Carl E. Arbesman, M.D., Buffalo, New York Reaginic antibodies to ragweed are known to be associated with immunoglobulin E. A question remains to be answered if reaginic antibodies to other allergens are also in the immunoglobulin E class. Sera of 12 patients allergic to, grass (3), house dust (1), caddis fly (2), cantaloupe (2), pike (1), egg (1), and penicillin (2), were examined by means of absorption with insoluble immunoadsorbents containing monospecific antiserum to IgE, IgG, IgA, IgM, and IgD. Prior to absorption, all patients’ sera, when examined by FTausnitz-Kustner (PK) test, demonstrated reaginic antibodies, in various titers, to the different allergens. To each immunoadsorbent, prepared by the method of Avrameas and Ternynck, an equal volume of a patient’s serum was added, shaken at 4°C overnight and the supernatants were tested for reaginic activity by the PK test. The immunoadsorbent containing antiserum to IgE was the only one to completely remove the detectable reaginic antibodies from the sera. There was some slight decrease in the reaginic titers of the sera absorbed by immunoadsorbents containing other than IgE antisera. These results indicate that the reaginic antibodies in sera of patients allergic to grasses, food, insects, house dust and penicillin are associated with IgE.
18
Evolution of the Identification of Allergen-Specific IgE Robert E. Reisman, MD, Clinical Professor of Pediatrics and Medicine, State University of New York at Buffalo, School of Medicine, Buffalo, NY In the late 1960s, IgE was isolated and characterized and found to have “reaginic” activity. The term reagin was used to identify the immunologic mediator of immediate hypersensitivity reactions. Reaginic antibodies were detected by the Prausnitz-Küstner (PK) reaction. This test was performed by passively sensitizing the skin of a nonallergic recipient with an intradermal injection of serum of an allergic person and challenging the test site 24 to 48 hours later with an injection of an allergen extract. An immediate wheal and flare reaction indicated a positive test. Before IgE was identified, IgA was thought to be the carrier of reaginic activity. The experiments described in this abstract were done after ragweedspecific IgE had been identified. The purpose was to determine whether reaginic antibodies reacting with other allergens were also IgE. The results indicated that a wide variety of allergic models—pollen, dust, food, insects, and drugs—were also mediated by allergen-specific IgE. Over the past 40 years, very refined techniques have evolved for detection and quantitation of allergen-specific IgE. It is the well documented mediator of immediate hypersensitivity reactions. Immune modifiers (omalizumab) have been developed and can decrease serum levels of allergen-specific IgE, providing clinical benefit. In retrospect, the data described in the abstract 40 years ago were the forerunners of the now well-recognized clinical significance of allergenspecific IgE. Disclosure of potential conflict of interest: R. E. Reisman has declared that he has no conflict of interest.
33
Immunologic Studies of lnsulin Allergy and Resistance
Robert E. Reisman, MD, Jerry Dolovich, M.O., J. David Schnatz, M.D., Yasuo Yagi, Ph.D., Carl E. Arbesman, M.D., Buffalo, New York An adult-onset diabetic received insulin for several months. Eight years later she developed generalized urticaria and angiodema 11 days after insulin was restarted. At the time of the urticaria, the serum was positive for insulin in Prausnitz-Küstner (PK) tests and the presence of IgE and IgG antibodies was demonstrated by radioimmunodiffusion (RID). Four days later, insulin resistance developed and 2000 units of insulin were given over an 18 hour period to control ketoacidosis. The urticaria disappeared and did not recur during a three month period of insulin therapy, yet the PK and intradermal skin tests remained positive. Despite the large amounts of insulin given and the diminution of allergic symptoms with the onset of insulin resistance, IgE antibody was still demonstrable. In addition, IgA, IgM and chiefly IgG antibodies were present at the height of the insulin resistance. After 4 weeks, the IgA and IgM antibodies were not detectable, but the IgG antibody remained in reduced amounts. Eight months after insulin therapy was stopped, generalized urticaria reappeared on two occasions following administration of small amounts of insulin. In summary, the development of insulin resistance was associated with the disappearance of a generalized allergic reaction to insulin despite the presence of serum IgE and PK antibodies and positive intradermal tests to insulin. The course of events is consistent with the postulate that IgG antibody has “blocking antibody” function in additional to an inhibition of the metabolic activity of the insulin.
Clinical Significance of Insulin Allergy and Insulin Resistance Studies: Application to Drug “Desensitization” Concept and Efficacy Robert E. Reisman, MD, Clinical Professor of Pediatrics and Medicine, State University of New York at Buffalo, School of Medicine, Buffalo, NY Allergic reactions to insulin are no longer a problem since replacement of animal-derived (bovine, porcine) insulins by human insulin. The relationship between the clinical reactions and the immunologic responses described in this abstract has significant current application to successful drug “desensitization” recommended for treatment of people who have prior suspected IgE-mediated allergic drug reactions. The reported patient initially had an allergic reaction to bovine insulin, mediated by IgE antibodies. Subsequently, she developed insulin resistance, which is mediated by high titers of insulin-specific IgG and necessitating extremely large doses of insulin for diabetic control. At that time, the allergic symptoms disappeared despite persistence of insulin-specific IgE. These observations suggest that the insulin-specific IgG also acted as a protective or blocking antibody, preventing the insulin-IgE antibody reaction and resulting allergic manifestations. This IgG antibody function is at least one suggested mechanism responsible for subsequent drug tolerance when people who have had prior suspected IgE-mediated allergic reactions are treated with a desensitization regime. In addition, there are similar corollaries, perhaps not as definitive, to successful venom immunotherapy and immunotherapy for inhalant allergens. Another relevant finding in this case is the difference in the persistence of IgE and IgG antibodies in the absence of drug exposure. Re-exposure to very small amounts of insulin on 2 occasions, about 8 months after daily insulin therapy was stopped, resulted in allergic reactions. At that time, insulin-specific IgE was still present (1 reaction was due to an insulin skin test—not in abstract). Insulin-specific IgG was present in very low titer S1
S2 AAAAI Abstracts from Yesteryear with Commentaries
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
about 8 months previously. These observations support the current recommendations that people who have had allergic drug reactions will need repeat desensitization each time the drug is prescribed. Also of interest was the detection of low titers of transient insulin-specific IgA and IgM. The significance of these antibodies is unknown, although there are similar findings in people with other allergies, such as ragweed pollen. This case study is an important contribution to defining the clinical approach and understanding the immunopathogenesis for successful drug tolerance for treatment of people with prior allergic reactions. Disclosure of potential conflict of interest: R. E. Reisman has declared that he has no conflict of interest.
47
Bronchial Challenge Testing in Asthma
Edwin A. Bronsky, M.D., and Elliot F. Ellis, M.D., Denver, Colorado We have investigated bronchial mucous membrane challenge tests in asthmatic children and compared the results with those obtained by skin testing. The subjects were 39 children ages 5-14 with severe perennial asthma hospitalized at the National Jewish Hospital in Denver. The patients subjected to challenges were either asymptomatic at the time of testing or under good control to minimize non-specfic reactions due toa hyperreactive airway. Aqueous allergen solutions in increasing concentrations were aerosolized by an air pump through a no. 40 DeVilbis nebulizer. Measurements of the change in expiratory flow were made with a Wright Peak Flow Meter. A reaction was considered to be positive only if a sustained decrease in expiratory flow of at least 25% was observed. When pollens, molds, and epidermals were used as test allergens negative bronchial challenge responses always resulted when the skin tests were negative. However, in the case of Endo house dust 3 of 7 patients gave a positive bronchial response when the skin test was negative. Overall positive bronchial challenge results were obtained in 61% of positive puncture test reactions. The correlation was poor in those instances in which the puncture tests were negative and only the intradermal test positive. In this situation a positive bronchial challenge could only be obtained in 21% of the positive intradermal tests. If results obtafned by this method are assumed to more clearly reflect the patients clinical sensitivity, then positive puncture tests have considerably more clinical significance than positive intradermal tests obtained in those instances when the puncture test to the same allergen has been negative.
Bronchial Challenge Testing in Asthma Edwin A. Bronsky, MD, Denver, Colo This research project was initiated in 1967 and completed in approximately 18 months. The purpose for the project was to identify what antigens may be allergic triggers for the patients’ asthma. Based on the results, we intended to make environmental control suggestions and to provide a formula for immunotherapy. In the late 1960s, the challenge methodology and the allergen solutions were not standardized as they are now. Even considering the antiquated challenge testing, the results were quite spectacular. The study clearly supported that puncture skin testing showed a greater sensitivity than intradermal testing, the latter being considered the more specific method at that time in diagnosing allergic causes of asthma. The bronchial challenge testing showed an excellent correlation between positive puncture testing and allergic asthma. The study resulted in a rapid decrease in the use of intradermal testing in many allergy offices. Noteworthy was the negative correlation. When properly done, it was rare to see a positive bronchial challenge in the presence of a negative skin test. Three of 7 positive challenges to Endo dust, which showed a negative skin reaction, may have been due to an irritant effect of the antigen rather than an allergic reaction. The irritant effect was suggested in the literature of the time. Pulmonary function was evaluated by a peak flow meter rather than using the more laborious spirometry of the era. With the equipment at the time of the study, not only was the use of spirometry extremely labor intensive for patients and physicians, but also the methodology rapidly resulted in exhaustion for the children, and it was obvious that this would not enable the study to be completed with a significant number of patients. The peak flow meter was chosen as the children used the meter 3 times a day for their entire residence at National Jewish Hospital. Repeated usage on the day of challenge did not lead to exhaustion, and each patient was able to complete the session until a positive result or the end of the testing occurred. The peak flow is not as sensitive as spirometry, which was potentially a difficulty. Over the subsequent decades, we have seen a dramatic improvement of allergy testing and bronchial provocation. Bronchial challenge testing has become more standardized, as well as standardization of pollen, dander, and other allergens. The big shortfall in technique 3-plus decades ago was the use of solutions of allergen as opposed to current the use of allergens in a more natural form. Allergen challenge rooms using pollens and dander have offered a much more natural setting for determining sensitivity. This has eliminated or reduced reliance on unintended alteration of the allergens, which in effect was not consistent with natural exposure. Disclosure of potential conflict of interest: E. A. Brodsky has declared that he has no conflict of interest.
IgE Associated with Reaginic Antibodies to Various Allergens Konrach Wicher, Ph.D., Koji Ito, M.D., Takeru Ishikawa, M.D., and Carl E. Arbesman, M.D., Buffalo, New York Reaginic antibodies to ragweed are known to be associated with immunoglobulin E. A question remains to be answered if reaginic antibodies to other allergens are also in the immunoglobulin E class. Sera of 12 patients allergic to, grass (3), house dust (1), caddis fly (2), cantaloupe (2), pike (1), egg (1), and penicillin (2), were examined by means of absorption with insoluble immunoadsorbents containing monospecific antiserum to IgE, IgG, IgA, IgM, and IgD. Prior to absorption, all patients’ sera, when examined by FTausnitz-Kustner (PK) test, demonstrated reaginic antibodies, in various titers, to the different allergens. To each immunoadsorbent, prepared by the method of Avrameas and Ternynck, an equal volume of a patient’s serum was added, shaken at 4°C overnight and the supernatants were tested for reaginic activity by the PK test. The immunoadsorbent containing antiserum to IgE was the only one to completely remove the detectable reaginic antibodies from the sera. There was some slight decrease in the reaginic titers of the sera absorbed by immunoadsorbents containing other than IgE antisera. These results indicate that the reaginic antibodies in sera of patients allergic to grasses, food, insects, house dust and penicillin are associated with IgE.
18
Evolution of the Identification of Allergen-Specific IgE Robert E. Reisman, MD, Clinical Professor of Pediatrics and Medicine, State University of New York at Buffalo, School of Medicine, Buffalo, NY In the late 1960s, IgE was isolated and characterized and found to have “reaginic” activity. The term reagin was used to identify the immunologic mediator of immediate hypersensitivity reactions. Reaginic antibodies were detected by the Prausnitz-Küstner (PK) reaction. This test was performed by passively sensitizing the skin of a nonallergic recipient with an intradermal injection of serum of an allergic person and challenging the test site 24 to 48 hours later with an injection of an allergen extract. An immediate wheal and flare reaction indicated a positive test. Before IgE was identified, IgA was thought to be the carrier of reaginic activity. The experiments described in this abstract were done after ragweedspecific IgE had been identified. The purpose was to determine whether reaginic antibodies reacting with other allergens were also IgE. The results indicated that a wide variety of allergic models—pollen, dust, food, insects, and drugs—were also mediated by allergen-specific IgE. Over the past 40 years, very refined techniques have evolved for detection and quantitation of allergen-specific IgE. It is the well documented mediator of immediate hypersensitivity reactions. Immune modifiers (omalizumab) have been developed and can decrease serum levels of allergen-specific IgE, providing clinical benefit. In retrospect, the data described in the abstract 40 years ago were the forerunners of the now well-recognized clinical significance of allergenspecific IgE. Disclosure of potential conflict of interest: R. E. Reisman has declared that he has no conflict of interest.
33
Immunologic Studies of lnsulin Allergy and Resistance
Robert E. Reisman, MD, Jerry Dolovich, M.O., J. David Schnatz, M.D., Yasuo Yagi, Ph.D., Carl E. Arbesman, M.D., Buffalo, New York An adult-onset diabetic received insulin for several months. Eight years later she developed generalized urticaria and angiodema 11 days after insulin was restarted. At the time of the urticaria, the serum was positive for insulin in Prausnitz-Küstner (PK) tests and the presence of IgE and IgG antibodies was demonstrated by radioimmunodiffusion (RID). Four days later, insulin resistance developed and 2000 units of insulin were given over an 18 hour period to control ketoacidosis. The urticaria disappeared and did not recur during a three month period of insulin therapy, yet the PK and intradermal skin tests remained positive. Despite the large amounts of insulin given and the diminution of allergic symptoms with the onset of insulin resistance, IgE antibody was still demonstrable. In addition, IgA, IgM and chiefly IgG antibodies were present at the height of the insulin resistance. After 4 weeks, the IgA and IgM antibodies were not detectable, but the IgG antibody remained in reduced amounts. Eight months after insulin therapy was stopped, generalized urticaria reappeared on two occasions following administration of small amounts of insulin. In summary, the development of insulin resistance was associated with the disappearance of a generalized allergic reaction to insulin despite the presence of serum IgE and PK antibodies and positive intradermal tests to insulin. The course of events is consistent with the postulate that IgG antibody has “blocking antibody” function in additional to an inhibition of the metabolic activity of the insulin.
Clinical Significance of Insulin Allergy and Insulin Resistance Studies: Application to Drug “Desensitization” Concept and Efficacy Robert E. Reisman, MD, Clinical Professor of Pediatrics and Medicine, State University of New York at Buffalo, School of Medicine, Buffalo, NY Allergic reactions to insulin are no longer a problem since replacement of animal-derived (bovine, porcine) insulins by human insulin. The relationship between the clinical reactions and the immunologic responses described in this abstract has significant current application to successful drug “desensitization” recommended for treatment of people who have prior suspected IgE-mediated allergic drug reactions. The reported patient initially had an allergic reaction to bovine insulin, mediated by IgE antibodies. Subsequently, she developed insulin resistance, which is mediated by high titers of insulin-specific IgG and necessitating extremely large doses of insulin for diabetic control. At that time, the allergic symptoms disappeared despite persistence of insulin-specific IgE. These observations suggest that the insulin-specific IgG also acted as a protective or blocking antibody, preventing the insulin-IgE antibody reaction and resulting allergic manifestations. This IgG antibody function is at least one suggested mechanism responsible for subsequent drug tolerance when people who have had prior suspected IgE-mediated allergic reactions are treated with a desensitization regime. In addition, there are similar corollaries, perhaps not as definitive, to successful venom immunotherapy and immunotherapy for inhalant allergens. Another relevant finding in this case is the difference in the persistence of IgE and IgG antibodies in the absence of drug exposure. Re-exposure to very small amounts of insulin on 2 occasions, about 8 months after daily insulin therapy was stopped, resulted in allergic reactions. At that time, insulin-specific IgE was still present (1 reaction was due to an insulin skin test—not in abstract). Insulin-specific IgG was present in very low titer S1
S2 AAAAI Abstracts from Yesteryear with Commentaries
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
about 8 months previously. These observations support the current recommendations that people who have had allergic drug reactions will need repeat desensitization each time the drug is prescribed. Also of interest was the detection of low titers of transient insulin-specific IgA and IgM. The significance of these antibodies is unknown, although there are similar findings in people with other allergies, such as ragweed pollen. This case study is an important contribution to defining the clinical approach and understanding the immunopathogenesis for successful drug tolerance for treatment of people with prior allergic reactions. Disclosure of potential conflict of interest: R. E. Reisman has declared that he has no conflict of interest.
47
Bronchial Challenge Testing in Asthma
Edwin A. Bronsky, M.D., and Elliot F. Ellis, M.D., Denver, Colorado We have investigated bronchial mucous membrane challenge tests in asthmatic children and compared the results with those obtained by skin testing. The subjects were 39 children ages 5-14 with severe perennial asthma hospitalized at the National Jewish Hospital in Denver. The patients subjected to challenges were either asymptomatic at the time of testing or under good control to minimize non-specfic reactions due toa hyperreactive airway. Aqueous allergen solutions in increasing concentrations were aerosolized by an air pump through a no. 40 DeVilbis nebulizer. Measurements of the change in expiratory flow were made with a Wright Peak Flow Meter. A reaction was considered to be positive only if a sustained decrease in expiratory flow of at least 25% was observed. When pollens, molds, and epidermals were used as test allergens negative bronchial challenge responses always resulted when the skin tests were negative. However, in the case of Endo house dust 3 of 7 patients gave a positive bronchial response when the skin test was negative. Overall positive bronchial challenge results were obtained in 61% of positive puncture test reactions. The correlation was poor in those instances in which the puncture tests were negative and only the intradermal test positive. In this situation a positive bronchial challenge could only be obtained in 21% of the positive intradermal tests. If results obtafned by this method are assumed to more clearly reflect the patients clinical sensitivity, then positive puncture tests have considerably more clinical significance than positive intradermal tests obtained in those instances when the puncture test to the same allergen has been negative.
Bronchial Challenge Testing in Asthma Edwin A. Bronsky, MD, Denver, Colo This research project was initiated in 1967 and completed in approximately 18 months. The purpose for the project was to identify what antigens may be allergic triggers for the patients’ asthma. Based on the results, we intended to make environmental control suggestions and to provide a formula for immunotherapy. In the late 1960s, the challenge methodology and the allergen solutions were not standardized as they are now. Even considering the antiquated challenge testing, the results were quite spectacular. The study clearly supported that puncture skin testing showed a greater sensitivity than intradermal testing, the latter being considered the more specific method at that time in diagnosing allergic causes of asthma. The bronchial challenge testing showed an excellent correlation between positive puncture testing and allergic asthma. The study resulted in a rapid decrease in the use of intradermal testing in many allergy offices. Noteworthy was the negative correlation. When properly done, it was rare to see a positive bronchial challenge in the presence of a negative skin test. Three of 7 positive challenges to Endo dust, which showed a negative skin reaction, may have been due to an irritant effect of the antigen rather than an allergic reaction. The irritant effect was suggested in the literature of the time. Pulmonary function was evaluated by a peak flow meter rather than using the more laborious spirometry of the era. With the equipment at the time of the study, not only was the use of spirometry extremely labor intensive for patients and physicians, but also the methodology rapidly resulted in exhaustion for the children, and it was obvious that this would not enable the study to be completed with a significant number of patients. The peak flow meter was chosen as the children used the meter 3 times a day for their entire residence at National Jewish Hospital. Repeated usage on the day of challenge did not lead to exhaustion, and each patient was able to complete the session until a positive result or the end of the testing occurred. The peak flow is not as sensitive as spirometry, which was potentially a difficulty. Over the subsequent decades, we have seen a dramatic improvement of allergy testing and bronchial provocation. Bronchial challenge testing has become more standardized, as well as standardization of pollen, dander, and other allergens. The big shortfall in technique 3-plus decades ago was the use of solutions of allergen as opposed to current the use of allergens in a more natural form. Allergen challenge rooms using pollens and dander have offered a much more natural setting for determining sensitivity. This has eliminated or reduced reliance on unintended alteration of the allergens, which in effect was not consistent with natural exposure. Disclosure of potential conflict of interest: E. A. Brodsky has declared that he has no conflict of interest.