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• W2024623971 abstract "“PROPHYLACTIC INOCULATIONS”In 1911, Leonard Noon of London published a short report on immunization treatment of hay fever with a distilled water extract of the pollen of timothy grass, Phleum pratense, which had been sealed in glass tubes and boiled for 10 minutes. Noon tested his patients by dropping dilutions of his extract in their eyes and observing the conjunctival reaction. Through this method he determined “the strength of the extract which is just sufficient to give this reaction.” His units represented the material extracted from 0.1 μg of pollen. He began inoculations at minute doses administered subcutaneously and increased the dose every 1 to 2 weeks, retesting the eye reaction to observe protection against the pollen “toxin.” The strength of the extract required to elicit an eye reaction was increased as much as 100-fold, and Noon hoped that the immunity thus demonstrated would be sufficient to carry the patients through a season “without suffering their annual attacks of hay fever.”1Noon L Prophylactic inoculation against hay fever.Lancet. 1911; 1: 1572-1573Abstract Google Scholar Noon, whose health was failing, turned the matter over to J. Freeman who, later the same year, reported results in 20 individuals with eye reactions to the extract who received doses varying from 4 to 2000 units. One patient dropped out of the study, but the remaining patients had decreased ocular reactivity: nine had “satisfactory” clinical results, five more had “moderately” or “fairly satisfactory” results, and the others had less than satisfactory results. Freeman recognized that “bias” could enter such an evaluation but thought that his patients gave “discriminating judgments.”2Freeman J Further observations on the treatment of hay fever by hypodermic inoculations of pollen vaccine.Lancet. 1911; 2: 814Abstract Google Scholar Noon and Freeman thought that hay fever resulted from a pollen toxin to which some people were “hypersensitive” and that their inoculations resulted in an “active immunity”.1Noon L Prophylactic inoculation against hay fever.Lancet. 1911; 1: 1572-1573Abstract Google Scholar, 2Freeman J Further observations on the treatment of hay fever by hypodermic inoculations of pollen vaccine.Lancet. 1911; 2: 814Abstract Google ScholarDESENSITIZATIONBy 1918, R. A. Cooke3Cooke RA Hay fever and asthma: the uses and limitations of desensitization.N Y Med J. 1918; 107: 577-583Google Scholar in the United States reported that it was generally accepted that allergic conditions such as hay fever and asthma were akin to anaphylaxis and resulted from antibodies produced after sensitizing exposures. Injections of extracts of not only airborne pollens but also animal danders, sachets, and foods were recommended. The mechanism was now considered to be “desensitization and not a true immunity,” which made it necessary to continue injections weekly. “Desensitization” had been described by Besredka and Steinhart4Besredka A Steinhart E Of anaphylaxis, of antianaphlaxis against horse serum, and the mechanism of antianaphylaxis.Ann Inst Pasteur. 1907; 21: 384-391Google Scholar as a tolerance achieved in anaphylactically sensitized animals after further nonfatal injections of the sensitizing antigen. In 1922, Cooke proposed revising the term as applied to treating allergic persons to “hyposensitization” because protection was less than complete.For a number of years, a continuing debate was carried on as to whether desensitization reduced immediate skin reactivity to the allergen, with strong proponents for the view that the minimum amount required to elicit a reaction was increased by 100-fold or more and equally strong proponents for the view that there was no change (reviewed by Harley5Harley D Hay fever: (I) The effect of pollen therapy on the skin reactions. (II) A reaction-inhibiting substance in the serum of treated patients.J Pathol. 1937; 44: 589-601Crossref Google Scholar). This issue was resolved more than 50 years later by definitive evidence that skin tests are reduced in ragweed and cat allergy.6Van Metre Jr, TE Marsh DG Adkinson Jr, NF Kagey-Sobotka A Khattignavong A Norman PS et al.Immunotherapy decreases skin sensitivity to cat extract.J Allergy Clin Immunol. 1989; 83: 888-899Abstract Full Text PDF PubMed Google Scholar, 7Van Metre TEJ Adkinson Jr, NF Kagey-Sobotka A Khattignavong A Marsh DG Norman PS et al.Immunotherapy decreases skin sensitivity to ragweed extract: demonstration by midpoint skin test titration.J Allergy Clin Immunol. 1990; 86: 587-588Abstract Full Text PDF PubMed Google ScholarBLOCKING ANTIBODIESIn 1921, Prausnitz and Kustner8Prausnitz C Kustner H Studies on supersensitivity.Centralbl f Bakteriol. 1921; 86: 160-169Google Scholar showed that anaphylactic sensitivity could be transferred by the serum of a sensitive patient if the recipient was a human being. The Prausnitz-Kustner reaction consisted of intradermal injection of a small amount of unheated serum from the allergic donor to a nonallergic recipient. After 24 hours, the antigen was injected into the same site and elicited an immediate wheal and erythema reaction. This work was performed with serum from Kustner, who was fish sensitive, but was soon extended to sensitivity to airborne allergens, most notably by de Besche.9deBesche A Studies on the reactions of asthmatics and on passive transference of hypersusceptibility.Am J Med Sci. 1923; 166: 265-275Crossref Google ScholarIn 1935, Cooke et al.10Cooke RA Barnard JH Hebald S Stull A Serological evidence of immunity with coexisting sensitization in a type of human allergy (hay fever).J Exp Med. 1935; 62: 733-751Crossref PubMed Google Scholar reported that blood transfusions from patients inoculated with ragweed extract would confer protection during the season to uninoculated patients. They further showed that serum from desensitized patients contained a specific factor, presumably antibody, which neutralized the Prausnitz-Kustner reaction, even though the titer of skin-sensitizing antibody was unchanged. The substance was found in the “pseudoglobulin” fraction and could be induced by immunization of nonallergic individuals by inoculation of large amounts of ragweed pollen extract.11Cooke RA Loveless M Stull A Studies on immunity in a type of human allergy (hay fever): serologic response of non-sensitive individuals to pollen injections.J Exp Med. 1937; 66: 689-696Crossref PubMed Google Scholar Loveless12Loveless MH Immunological studies of pollinosis: I. The presence of two antibodies related to the same pollen-antigen in the serum of treated hay-fever patients.J Immunol. 1940; 38: 25-50Google Scholar demonstrated that these “blocking” antibodies were stable to heating at 56° C and confirmed their specificity. Although it was hoped that blocking antibodies would explain clinical improvement after desensitization, several studies dashed this hope because there seemed to be little relationship between improvement and blocking activity.13Loveless MH Immunological studies of pollinosis: IV. The relationship between thermostable antibody in the circulation and clinical immunity.J Immunol. 1943; 47: 165-180Google Scholar, 14Scully MA Rackemann FM Studies on the blocking antibody of Cooke in the treatment of hay fever.J Allergy. 1941; 12: 549-558Abstract Full Text PDF Google Scholar, 15Sherman WB Stull A Cooke RA Serologic changes in hay fever cases treated over a period of years.J Allergy. 1940; 11: 225-244Abstract Full Text PDF Google ScholarAt the same time, it was becoming apparent that skin-sensitizing antibodies were often initially raised during desensitization and then, after a year or more of treatment, might decline.15Sherman WB Stull A Cooke RA Serologic changes in hay fever cases treated over a period of years.J Allergy. 1940; 11: 225-244Abstract Full Text PDF Google Scholar, 16Gay LN Chant E The passive transfer of hypersensitivity (local and contralateral passive transfer experiments).Bull Johns Hopkins Hosp. 1927; 40: 270-286Google Scholar, 17Levine P Coca AF Studies on hypersensitiveness. XXII. On the nature of the alleviating effect of the specific treatment of atopic conditions.J Immunol. 1926; 11: 449-464Google Scholar, 18Markin LE Report of 100 cases of local passive transfer of hypersensitiveness.J Allergy. 1931; 2: 285-290Abstract Full Text PDF Google Scholar, 19Sherman WB Changes in serological reactions and tissue sensitivity in hay fever patients during the early months of treatment.J Immunol. 1941; 40: 289-309Google Scholar In 1964, a thorough study of sera from patients treated with ragweed extract for as long as 20 years showed a progressive decline in skin-sensitizing antibody. Notably, however, a number of patients still had easily detectable, even high, titers after many years of injections.20Connell JT Skin-sensitizing antibody titer: III. Relationship of the skin-sensitizing antibody titer to the intracutaneous skin test, to the tolerance of injections of antigens, and to the effects of prolonged treatment with antigen.J Allergy. 1964; 35: 169-176Abstract Full Text PDF PubMed Google ScholarCONTROLLED STUDIESIn the 1950s, the lack of control observations in untreated patients began to be appreciated, and therefore several clinics started controlled studies. Feinberg et al.21Feinberg SM Stier RM Grater WC A suggested quantitative evaluation of the degree of sensitivity of patients with ragweed pollinosis.J Allergy. 1952; 23: 387-394Abstract Full Text PDF PubMed Google Scholar compared reactivity to dilutions of ragweed extract either inhaled, applied to the eye, or dropped on the nasal mucosa in control subjects and patients inoculated for a year or more. The treated group showed less reactivity at all three sites.Frankland and Augustin22Frankland AW Augustin R Prophylaxis of summer hay-fever and asthma: a controlled trial comparing crude grass-pollen extracts with the isolated main protein component.Lancet. 1954; 1: 1055-1057Abstract Google Scholar carried out the first trial with placebo treatment and blinded observations to eliminate bias. Two hundred patients with grass pollen fever, asthma, or both were treated with either active timothy and cocksfoot grass extracts or placebos consisting of histamine or inactivated extract. Seventy-nine percent of those with hay fever had either good or excellent results after pollen treatment, whereas only 33% reported good results after the placebos. Results with asthma were more striking: 94% of those receiving the active material had good or excellent results, whereas only 30% of those who received placebos reported similar results.Johnstone23Johnstone DE Study of the role of antigen dosage in the treatment of pollenosis and pollen asthma.J Dis Child. 1957; 94: 1-5PubMed Google Scholar studied both hay fever and asthma caused by ragweed pollen in 112 children. One group received the highest tolerated dose of ragweed pollen extract, and the remaining patients were divided into three groups, receiving either placebos or tiny doses of extract. According to the responses of the subjects’ mothers to questionnaires, the improvement of hay fever symptoms was greater in the high dose group than in the low dose and placebo groups. Sixty-eight percent of the high dose group lost their asthma, whereas only 19% and 7% of the low dose and placebo groups did so (p < 0.001).Lowell and Franklin24Lowell FC Franklin W A “double blind” study of treatment with aqueous allergenic extracts in cases of allergic rhinitis.J Allergy. 1963; 34: 165-182Abstract Full Text PDF Google Scholar compared ragweed pollen extract with a placebo of histamine in patients with ragweed-induced hay fever over two seasons. Symptom scores from daily diaries were significantly lower in the specifically treated group during the weeks of maximum ragweed pollination. In a separate study Lowell and Franklin25Lowell FC Franklin W A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever.N Engl J Med. 1965; 273: 675-679Crossref PubMed Google Scholar also tested clinical specificity. In patients with multiple sensitivities who were receiving injections of multiple allergens, immunization with ragweed extract was withdrawn in some patients in a double-blind fashion while being continued in others. Five months after this maneuver, the fall symptoms were significantly less severe in those who continued to receive ragweed extract than in those who did not, indicating not only that treatment with other allergens did little for ragweed symptoms but also that the results of ragweed treatment relapsed after 5 months or less.Fontana et al.26Fontana VJ Holt Jr, LE Mainland D Effectiveness of hyposensitization therapy in ragweed hay-fever in children.J Am Med Assn. 1965; 195: 985-992Crossref Google Scholar countered these favorable studies by a 5-year study of ragweed extract in childhood hay fever comparing placebos and active extract. Weekly symptom cards filled out by parents reported the number of days the patient had hay fever without distinguishing mild from severe symptoms. The number of days of symptoms was not different in the placebo and treated groups, even though skin test reactivity declined in the treated group. A degree of relief less than complete was not looked for, making the apparent negative result easily explained.IMMUNOLOGIC CORRELATESBy 1960, immunologic methods were developed sufficiently to allow in vitro measurements. Arbesman et al.27Arbesman CE Kantor SZ Rapp D Rose NR Immunologic studies of ragweed-sensitive patients: III. Clinical aspects: the relationship of reagin and hemagglutinating antibody titers to results of hyposensitization therapy.J Allergy. 1960; 31: 342-350Abstract Full Text PDF PubMed Google Scholar measured serum antibody by hemagglutination of tanned red cells sensitized with ragweed extract and noted that nearly every ragweed-sensitive patient had hemagglutinating antibodies, whereas only about 15% of normal subjects did so. After desensitization, the rise in titer varied from onefold to eightfold. There was no apparent relationship with clinical results or change in skin-sensitizing antibody. They also noted that larger doses of extract gave greater relief of symptoms.A technique for chemically measuring histamine allowed Van Arsdel and Middleton28Van Arsdel Jr, PP Middleton Jr, E The effect of hyposensitization on the in vitro histamine release by specific antigen.J Allergy. 1961; 32: 348-356Abstract Full Text PDF PubMed Google Scholar to examine histamine release from cells in whole blood in the presence of specific allergen before and after treatment with ragweed extract. Histamine release was completely abolished in a few patients and was reduced in others.Lichtenstein and Osler29Lichtenstein LM Osler AG Studies of the mechanism of hypersensitivity phenomena: IX. Histamine release from human leukocytes by ragweed pollen antigen.J Exp Med. 1964; 120: 507-530Crossref PubMed Google Scholar developed a method for preparing isolated washed peripheral blood leukocytes for measurement of histamine release that allowed a more discriminating look at changes in mediator release. It is now recognized that histamine resides in the basophils and that these studies represent release of mediators from IgE-sensitized basophils.30Ishizaka T DeBernardo R Tomioka H Lichtenstein LM Ishizaka K Identification of basophil granulocytes as a site of allergic histamine release.J Immunol. 1972; 108: 1000-1008PubMed Google Scholar The method could also be applied to blocking antibody in serum by adding dilutions of serum to allergic cells and measuring inhibition of histamine release.31Lichtenstein LM Osler AG Studies of the mechanisms of hypersensitivity phenomena: XII. An in vitro study of the reaction between ragweed pollen antigen, allergic human serum and ragweed sensitive human leukocytes.J Immunol. 1966; 96: 169-179PubMed Google Scholar Isolation of the major allergen of ragweed antigen E (now known as Amb a 1) by King et al.32King TP Norman PS Connell JT Isolation and characterization of allergens from ragweed pollen II.Biochemistry. 1964; 3: 458-468Crossref PubMed Google Scholar allowed not only immunologic quantification but also standardization of ragweed extracts. A symptom diary developed by Rhyne assessed the severity of disease.33Norman PS Rhyne MB Mellits D Evaluation of agents for the treatment of seasonal respiratory allergies.in: Clinical pharmacology. : Pergamon Press, Oxford1966: 639-652Google Scholar With these techniques, in a double-blind study comparing preseasonal inoculations of crude ragweed extract, Amb a 1, or placebos, several findings emerged. In untreated patients, preseasonal basophil sensitivity to Amb a 1 correlated with symptom-medication scores obtained during natural exposure. Treatment with crude ragweed extract or Amb a 1 resulted in reduction of cellular sensitivity in some patients. Treated patients showed little correlation between cellular sensitivity and symptom scores but invariably had a rise in blocking antibody.31Lichtenstein LM Osler AG Studies of the mechanisms of hypersensitivity phenomena: XII. An in vitro study of the reaction between ragweed pollen antigen, allergic human serum and ragweed sensitive human leukocytes.J Immunol. 1966; 96: 169-179PubMed Google Scholar After these results, we began to use the term immunotherapy to describe the process because it clearly led to complex immunologic changes.Soon thereafter, Pruzansky and Patterson34Pruzansky JJ Patterson R Histamine after release from leukocytes of hypersensitive individuals: reduced sensitivity of leukocytes after injection therapy.J Allergy. 1967; 39: 44-50Abstract Full Text PDF PubMed Google Scholar reported on four patients with hay fever, several of whom had complete ablation of basophil reactivity after much larger doses of ragweed extract along with a rise in antibodies that blocked ragweed-induced histamine release. A subsequent study by Lichtenstein et al.35Lichtenstein LM Norman PS Winkenwerder WL Clinical and in vitro studies on the role of immunotherapy in ragweed hay fever.Am J Med. 1968; 44: 514-524Abstract Full Text PDF PubMed Google Scholar showed that larger doses of either ragweed extract or Amb a 1 than that used in their initial study produced significantly lower seasonal symptoms scores than placebos. These doses produced complete loss of cellular sensitivity in some patients and greater blocking antibody responses in all. In addition, when no injections were administered between seasons, blocking antibody titers began to decline in a few months.36Lichtenstein LM Norman PS Winkenwerder WL A single year of immunotherapy for ragweed hay fever. Immunologic and clinical studies.Ann Intern Med. 1971; 75: 663-671Crossref PubMed Google Scholar Another article described results in patients followed-up over several years and demonstrated that increasing doses in preseasonal courses resulted in a greater difference between placebo- and ragweed-treated patients (see Figure on Journal cover).37Norman PS Winkenwerder WL Lichtenstein LM Maintenance immunotherapy in ragweed hay fever. Booster injections at six week intervals.J Allergy. 1971; 47: 273-282PubMed Google Scholar Furthermore, blocking antibody levels and clinical relief could be maintained by booster injections given every 6 weeks.37Norman PS Winkenwerder WL Lichtenstein LM Maintenance immunotherapy in ragweed hay fever. Booster injections at six week intervals.J Allergy. 1971; 47: 273-282PubMed Google Scholar Separation studies and animal sera against immunoglobulin classes demonstrated that blocking antibodies are mostly, if not entirely, IgG.38Lichtenstein LM A quantitative in vitro study of the chromatographic distribution and immunoglobulin characteristics of human blocking antibody.J Immunol. 1968; 101: 317-324PubMed Google ScholarIn children, Sadan et al.39Sadan N Rhyne MB Mellits ED Goldstein EO Levy DA Lichtenstein LM Immunotherapy of pollinosis in children. Investigation of the immunologic basis of clinical improvement.N Engl J Med. 1969; 280: 623-627Crossref PubMed Google Scholar confirmed the immunologic findings and the clinical efficacy of preseasonal inoculations. Neither changes in cell sensitivity nor blocking antibody correlated with symptoms scores. Lichtenstein et al.36Lichtenstein LM Norman PS Winkenwerder WL A single year of immunotherapy for ragweed hay fever. Immunologic and clinical studies.Ann Intern Med. 1971; 75: 663-671Crossref PubMed Google Scholar reexamined this question in newly treated adult patients and showed that high levels of blocking antibody response more often were accompanied by low symptom scores but that titers often failed to predict clinical results in individual patients.Serial determinations of IgG antibodies in patients undergoing ragweed immunotherapy indicate that titers reach a maximum peculiar to each patient in the first year or two and then show little further rise no matter how vigorous or frequent the dosage.40Norman PS Lichtenstein LM The clinical and immunologic specificity of immunotherapy.J Allergy Clin Immunol. 1978; 61: 370-377Abstract Full Text PDF PubMed Google Scholar The same phenomenon has been noted with immunization to insect venoms.IgE ANTIBODIESPassive transfer of skin-sensitizing antibodies from the serum of allergic individuals to the cells of nonallergic individuals could be accomplished with sufficient regularity to use the release of histamine as a measure of the antibody transferred. Levy and Osler41Levy DA Osler AG Studies on the mechanism of hypersensitivity phenomena. XVI. In vitro assays of reaginic activity in human sera: effect of therapeutic immunization on seasonal titer changes.J Immunol. 1967; 99: 1068-1077PubMed Google Scholar reported that seasonal exposure to ragweed pollen regularly caused a rise in transferable antibodies in allergic persons, which then declined slowly over the intervening months until the next exposure. After immunotherapy, the rise resulting from seasonal exposure was blunted or failed to occur. A study in children confirmed this and noted that postseason titers of transferable antibody were lower than pretreatment titers.42Levy DA Lichtenstein LM Goldstein EO Ishizaka K Immunologic and cellular changes accompanying the therapy of pollen allergy.J Clin Invest. 1971; 50: 360-369Crossref PubMed Google ScholarThe identification of reagins as belonging to a unique class of antibodies named immunoglobulin E (IgE)43Ishizaka K Ishizaka T Identification of gamma E-antibodies as a carrier of reaginic activity.J Immunol. 1967; 99: 1187-1198PubMed Google Scholar, 44Ishizaka K Ishizaka T Terry WD Antigenic structure of gamma E-globulin and reaginic antibody.J Immunol. 1967; 99: 849-858PubMed Google Scholar, 45Johansson SGO Raised levels of a new immunoglobulin class (IgND) in asthma.Lancet. 1967; 2: 951Abstract PubMed Google Scholar and the development of a solid phase radioimmunoassay for specific IgE antibodies (radioallergosorbent test or RAST)46Wide L Bennich H Johannson SGO Diagnosis of allergy by an in vitro test for allergen antibodies.Lancet. 1967; 2: 1105Abstract PubMed Google Scholar allowed a more discriminating investigation of the effect of immunotherapy on antibodies. In patients with ragweed hay fever, serial determinations of IgE antibodies confirmed that seasonal exposure resulted in a rise in titer followed by a slow decline until the next season. Immunotherapy resulted in an initial rise in titer, a blunting or absence of the seasonal rise, and eventual decline below pretreatment levels, although the antibodies continued to be present. The drop in IgE antibody was significantly correlated with the posttreatment titer of blocking antibodies.47Lichtenstein LM Ishizaka K Norman PS Sobotka AK Hill BM IgE antibody measurements in ragweed hay fever. Relationship to clinical severity and the results of immunotherapy.J Clin Invest. 1973; 52: 472-482Crossref PubMed Google Scholar Yunginger and Gleich48Yunginger JW Gleich GJ Seasonal changes in IgE antibodies and their relationship to IgG antibodies during immunotherapy for ragweed hay fever.J Clin Invest. 1973; 52: 1268-1275Crossref PubMed Google Scholar found a direct relationship between pretreatment IgE titer and IgG titer after treatment. In a subsequent study Gleich et al.49Gleich GJ Jacob GL Yunginger JW Henderson LL Measurement of the absolute levels of IgE antibodies in patients with ragweed hay fever: effect of immunotherapy on seasonal changes and relationship to IgG antibodies.J Allergy Clin Immunol. 1977; 60: 188-198Abstract Full Text PDF PubMed Google Scholar found that untreated patients with high levels of IgE antibody had greater seasonal rises and postseason declines in IgE titer. Treatment more successfully inhibited seasonal rises in patients with low specific IgE antibody. They noted no relationship between decline of serum IgE antibody and relief of symptoms.EARLY EVALUATION OF LYMPHOCYTE REACTIONSAllergic patients not only have antibodies but also exhibit altered lymphocyte reactivity to specific allergens. Rocklin et al.50Rocklin RE Pence H Kaplan H Evans R Cell-mediated immune response of ragweed-sensitive patients to ragweed antigen E: in vitro lymphocyte transformation and elaboration of lymphocyte mediators.J Clin Invest. 1974; 53: 735-744Crossref PubMed Google Scholar demonstrated that blood lymphocytes of allergic patients incubated in vitro with allergen show enhanced proliferation and production of mediators (mitogenic factor and macrophage inhibition factor). After immunotherapy with ragweed extract, these functions decreased.51Evans R Pence H Kaplan H Rocklin RE The effect of immunotherapy on humoral and cellular responses in ragweed hay fever.J Clin Invest. 1976; 57: 1378-1385Crossref PubMed Google Scholar Subsequently, Rocklin et al.52Rocklin RE Sheffer AL Greineder DK Melmon KL Generation of antigen-specific suppressor cells during allergy desensitization.N Engl J Med. 1980; 302: 1213-1219Crossref PubMed Google Scholar studied allergen-induced lymphocyte proliferation in vitro and showed that there was an increase in the activity of antigen-specific suppressor cells after 6 and 12 months of immunotherapy.In recent years there has been extensive study of changes in inflammatory cell and lymphocyte responses after immunotherapy. These are to be covered in a subsequent review. The observation that late-phase skin responses to intradermal allergen are virtually obliterated after immunotherapy53Pienkowski MM Adkinson Jr, NF Plaut M Norman PS Lichtenstein LM Prostaglandin D2 and histamine during the immediate and the late-phase components of allergic cutaneous responses.J Allergy Clin Immunol. 1988; 82: 95-100Abstract Full Text PDF PubMed Google Scholar, 54Iliopoulos O Proud D Adkinson Jr, NF Creticos PS Norman PS Kagey-Sobotka A et al.Effects of immunotherapy on the early, late and rechallenge nasal reaction to provocation with allergen: changes in inflammatory mediators and cells.J Allergy Clin Immunol. 1991; 87: 855-866Abstract Full Text PDF PubMed Google Scholar provided a stimulus for such studies.CHALLENGE TECHNIQUESNaclerio et al.55Naclerio RM Meier HL Kagey-Sobotka A Adkinson Jr, NF Meyers DA Norman PS et al.Mediator release after nasal airway challenge with allergen.Am Rev Respir Dis. 1983; 128: 597-602PubMed Google Scholar developed a nasal challenge method that uses graded nasal exposure to either whole pollen or pollen extracts followed by measurement of mediators appearing in nasal secretions. To determine whether specific immunotherapy alters in vivo mediator release, Creticos et al.56Creticos PS Adkinson Jr, NF Kagey-Sobotka A Proud D Meier HL Naclerio RM et al.Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy.J Clin Invest. 1985; 76: 2247-2253Crossref PubMed Google Scholar compared untreated subjects allergic to ragweed with patients receiving long-term immunotherapy with ragweed extract (median dose = 6 μg Amb a 1). Patients receiving immunotherapy required larger threshold pollen doses not only to provoke sneezing but also to elicit release of the mediators. At any given dose, the treated groups released less mediator. In a prospective study patients starting immunotherapy were challenged serially over many months and showed increasing thresholds for mediator release as the therapeutic dose was raised. At a dose equivalent to 0.6 μg Amb a 1 there was little change in the response, but at 12.4 μg there was a significant reduction in mediator release. A further increase of the treatment dose to 24.8 μg produced little additional change.57Creticos PS Marsh DG Proud D Kagey-Sobotka A Adkinson Jr, NF Friedhoff L et al.Responses to ragweed-pollen nasal challenge before and after immunotherapy.J Allergy Clin Immunol. 1989; 84: 197-205Abstract Full Text PDF PubMed Google ScholarStudies of immunotherapy of asthma show that the threshold for the immediate airways constriction response to aerosol challenge with extracts is increased after immunotherapy with extracts of house dust,58Åas K Hyposensitization in house dust allergy asthma: a double blind controlled study with evaluation of the effect on bronchial sensitivity to house dust.Acta Paediatr Scand. 1971; 60: 264-268Crossref PubMed Google Scholar cat pelt,59Taylor WW Ohman JL Lowell FC Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of bronchial responses to cat allergen and histamine.J Allergy Clin Immunol. 1978; 61: 283-287Abstract Full Text PDF PubMed Google Scholar and ragweed pollen.60Creticos PS Reed CE Norman PS The NIAID cooperative study of the role of immunotherapy in seasonal ragweed-induced adult asthma [abstract].J Allergy Clin Immunol. 1993; 91: 226Google Scholar Mediator measurement has yet to be done.SPECIFICITY OF IMMUNOTHERAPYNorman and Lichtenstein40Norman PS Lichtenstein LM The clinical and immu" @default.
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• W2024623971 modified "2023-09-24" @default.
• W2024623971 title "Immunotherapy: Past and present" @default.
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