Narrative review traces the clinical efficacy and immunological mechanisms of allergen immunotherapy in allergic disease, highlighting antibody modulation and cellular desensitization.
"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 this in treated patients and showed that high levels of blocking antibody response more often were by low symptom scores but that titers often to clinical results in of antibodies in patients ragweed immunotherapy that titers a maximum to patient in the first year or two and little further rise no matter or the PS Lichtenstein LM The clinical and immunologic specificity of Allergy Clin Immunol. Full Text PDF PubMed Google Scholar The same been noted with immunization to transfer of skin-sensitizing antibodies from the serum of allergic individuals to the cells of nonallergic individuals could be with sufficient to use the release of histamine as a of the antibody Levy and DA Osler AG Studies on the mechanism of hypersensitivity In vitro of in human effect of immunization on seasonal titer Immunol. 1967; Google Scholar reported that seasonal to ragweed pollen caused a rise in antibodies in allergic which declined over the months the exposure. After the rise from seasonal was or to A study in confirmed this and noted that titers of antibody were lower than DA Lichtenstein LM Goldstein EO Ishizaka K Immunologic and cellular changes the therapy of pollen Clin 1971; PubMed Google of as to a of antibodies immunoglobulin E K Ishizaka T Identification of as a of Immunol. 1967; Google Scholar, K Ishizaka T of and antibody.J Immunol. 1967; Google Scholar, levels of a immunoglobulin in 1967; 2: PubMed Google Scholar and the of a for specific antibodies test or L H of allergy by an in vitro test for allergen 1967; 2: PubMed Google Scholar allowed a more discriminating of the effect of immunotherapy on In patients with ragweed hay fever, of antibodies confirmed that seasonal resulted in a rise in titer by a decline the Immunotherapy resulted in an initial rise in a or of the seasonal and decline the antibodies continued to be The in antibody was significantly correlated with the titer of blocking LM Ishizaka K Norman PS antibody in ragweed hay fever. Relationship to clinical severity and the results of Clin PubMed Google Scholar and changes in antibodies and their relationship to antibodies during immunotherapy for ragweed hay fever.J Clin PubMed Google Scholar found a relationship between titer and titer after In a subsequent study et of the levels of antibodies in patients with ragweed hay fever: effect of immunotherapy on seasonal changes and relationship to Allergy Clin Immunol. Full Text PDF PubMed Google Scholar found that untreated patients with high levels of antibody had greater seasonal and in Treatment more seasonal in patients with low specific antibody. They noted no relationship between decline of serum antibody and relief of patients not only antibodies but also reactivity to specific et H H R response of ragweed-sensitive patients to ragweed antigen in vitro and of Clin PubMed Google Scholar demonstrated that blood of allergic patients in vitro with allergen and of mediators and inhibition After immunotherapy with ragweed extract, these R H H The effect of immunotherapy on and cellular responses in ragweed hay fever.J Clin PubMed Google Scholar et of cells during allergy desensitization.N Engl J Med. PubMed Google Scholar studied in vitro and showed that there was an in the of cells after 6 and months of years there been study of changes in cell and responses after These are to be in a subsequent The that skin responses to intradermal allergen are after Adkinson Jr, NF M Norman PS Lichtenstein LM and histamine during the immediate and the of allergic Allergy Clin Immunol. Full Text PDF PubMed Google Scholar, D Adkinson Jr, NF PS Norman PS Kagey-Sobotka A et of immunotherapy on the and nasal reaction to with changes in mediators and Allergy Clin Immunol. Full Text PDF PubMed Google Scholar a for such et RM Kagey-Sobotka A Adkinson Jr, NF DA Norman PS et release after nasal with Google Scholar developed a nasal method that uses nasal to either whole pollen or pollen extracts by measurement of mediators in nasal whether specific immunotherapy in mediator et PS Adkinson Jr, NF Kagey-Sobotka A D RM et with ragweed pollen in hay fever patients. of Clin PubMed Google Scholar compared untreated subjects allergic to ragweed with patients receiving immunotherapy with ragweed extract dose 6 μg Amb a receiving immunotherapy required larger pollen doses not only to but also to elicit release of the given the treated groups less In a study patients immunotherapy were over many months and showed increasing for mediator release as the dose was a dose to μg Amb a 1 there was little change in the but at μg there was a reduction in mediator release. A further of the treatment dose to μg produced little PS Marsh DG D Kagey-Sobotka A Adkinson Jr, NF L et to nasal before and after Allergy Clin Immunol. 1989; Full Text PDF PubMed Google of immunotherapy of asthma that the for the immediate response to with extracts is increased after immunotherapy with extracts of K in allergy asthma: a controlled study with evaluation of the effect on sensitivity to 1971; PubMed Google Scholar cat Lowell FC Immunotherapy in trial with evaluation of responses to cat allergen and Allergy Clin Immunol. Full Text PDF PubMed Google Scholar and ragweed PS CE Norman PS The study of the role of immunotherapy in seasonal ragweed-induced asthma Allergy Clin Immunol. Scholar measurement to be and PS Lichtenstein LM The clinical and
No takes yet. Share an insight, caveat, or question.
Philip S. Norman (1998) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: