Immunotherapy Philip S. Norman,
for nasal allergy
Controlled studies establish the effectiveness of immunotherapy for allergic rhinitis related to grasses, ragweed, mountain cedar, and birch pollens. Clinical improvement appears to be specific, to require adequate dosage, and to relapse once booster injections are discontinued. Specific immunologic responses increase blocking IgG antibodies in serum and secretions, blunt IgE responses, and reduce lymphocyte reactions. Immediate mediator release is reduced both in basophils challenged in vitro and in nasal secretions after local challenge in vivo. Effects on late-phase inflammatory reactions are still under investigation. Standardization of allergenic extracts by immunologic methods should make useful therapeutic responses more frequent. (J ALLERGYCLINIMMUNOL 1988;81:992-6.)
Immunotherapy has long been used in an attempt to block the human allergic response to inhaled allergens. Although demonstrably successful in some specific clinical situations, its place in the overall management of allergic conditions is more than a little controversial. Opinions vary from complete rejection of the method for any purpose (a view held by many who are not allergists) to almost ritual use in any patient with upper or lower respiratory tract symptoms that are even vaguely allergic. Controlled clinical studies of immunotherapy in model conditions such as ragweed hay fever demonstrate that: (1) clinical results depend on adequate dosage, with small doses having a poor rate of success or being totally ineffective’, ‘; (2) relapse may occur once booster injections are discontinued3; and (3) results are specific, being effective only for the allergen(s) being administered, and ineffective for excluded allergens.‘, 4 Immunologically, a variety of changes have been demonstrated that may in part be responsible for relief of allergic symptoms: (1) rise in serum IgG “blocking” antibodies; (2) suppression in the usual seasonal rise in IgE antibodies that follows environmental exposure, and a slow decline during several years in the
From the Department of Medicine, Division of Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore. Publication No. 715 from the O’Neill Research Laboratories at The Good Samaritan Hospital, Baltimore. Supported by Grants AI 20136 and AI 04866 from the National Institutes of Health. Reprint requests: Philip S. Norman, MD, The Johns Hopkins University School of Medicine at The Good Samaritan Hospital, 5601 Loch Raven Blvd., Baltimore, MD 21239.
Toluenesulfonylarginine methyl ester
level of specific IgE antibodies (although complete disappearance is rare); (3) increase in blocking IgA and IgG antibodies in secretions; (4) reduced basophil reactivity and sensitivity to allergens (as determined by in vitro leukocyte histamine release studies); and (5) reduced in vitro lymphocyte responsiveness to allergens.5-7 Each of these changes may not be seen in every patient, and those that are important in ameliorating symptoms are not well defined. One change, however, that has some correlation with clinical results has been the titer of serum “blocking” antibodies.8 Measurement of these serum IgG antibodies shows that once an adequate dosage is reached, these levels reach a plateau and are unlikely to rise much higher no matter how large a dose is administered. Fig. 1 shows serial measurements of specific IgE and IgG antibodies in serum in a patient undergoing immunotherapy for the first time, and illustrates this point9 Current evidence suggests that the reason for a favorable clinical response to immunotherapy lies in altering the balance between noxious responses to allergen mediated by IgE antibodies and protective immunologic responses mediated by IgG and probably other as yet incompletely defined mechanisms. No immunologic test or combination of tests predicts accurately how an immunized patient will respond to an allergic exposure. It can be said, however, that a dose that fails to induce an increase in IgG antibody will fail to afford relief.
,JOLLiME 81 YUMBER 5. PART 2
Fig. 1. Serologic responses in patient receiving ragweed immunotherapy. Bottom pane/, Individual and cumulative doses of ragweed extract in micrograms of antigen E. Top pane/, Serum levels of IgE and IgG antibodies to ragweed and total IgE. LL, Large local reaction. (From Creticos PS, Van Metre TE, Mardiney MR. et al. J ALLERGY CLIN IMMUNOL 1984;73:94-104.)
Further elucidation of responses to injection therapy will depend on the development of techniques for the evaluation of patient responses that are more precise than the by now traditional symptom diaries that have been in use for 20 years or more. If we did not already realize it from skin test data, the use of IgE measurements for the quantitation of sensitivity to any one allergen shows that it varies greatly among patients. Furthermore, patients vary in what they are sensitive to and in the clinical manifestations of the response. These variables interfere with attempts to assess responses to treatment accurately, because changes induced by treatment are lost in the multitude of other events that may influence the manifestations that the patient and physician perceive as disease. For example, evaluation of immunotherapy with a specific extract is hampered because most allergic patients have multiple allergies, whereas the treatment has the expected immunologic specificity. According to symptom diary studies, treatment with a particular extract furnishes, at best, less than complete relief of symptoms attributed to that allergen. Such a result may be attributed either to the inherent limitation of immunotherapy or to failure to treat with all the allergens relevant to symptoms. Purely clinical observations of disease during natural exposure cannot distinguish between these possibilities. On the other hand, a laboratory challenge performed when the patient is asymptomatic reproduces the disease related to single allergen exposure for a distinct time interval, and thus should be a better way to assess the extent
to which patients are protected by specific immunotherapy against specific exposure. A series of studies initiated by Naclerio et al. I” show that when sensitive persons are challenged intranasally with pollen, they release the panoply of mediators that are produced by mast cells and basophils. These mediators are readily detected in nasal secretions, and those found in immediate reactions to date include histamine, PGDz, TAME-esterases,‘” kinins,” PGE, 6-keto-PGF,, and peptide leukotrienes.‘” Although not all of these mediators necessarily come from mast cells, it appears clear that the primary occurrence is mast cell mediator release, even if some of these mediators are then secondarily synthesized or activated. Furthermore, there is an outpouring of serum proteins, as indicated by increased amounts of serum albumin. These proteins include kininogen, thus providing the substrate for kinin conversion. ii Mediators and proteins appear within minutes after challenge. when sneezing and other symptoms are maximal, and disappear 10 to 30 minutes after challenge is discontinued. To determine whether specific immunotherapy aiters this in vivo mediator release, we compared 27 untreated highly sensitive ragweed-allergic patients with 12 similarly sensitive patients receiving longterm immunotherapy with ragweed extract (median dose 6 mg ragweed antigen E). The two groups were equally sensitive by skin tests and basophil histamine release. Fig. 2. shows that patients receiving immunotherapy required larger threshold polien doses, not
J. ALLERGY CLIN. IMMUNOL. MAY 1988
HISTAMINE Nontreated Group o Trcotcd Group
Fig. 2. Cumulative patients threefold challenge
percent of untreated (0) and treated (01 sneezing or demonstrating mediator release (a rise over baseline) at each respective pollen dose.
only to provoke sneezing but also to elicit release of TAME-esterase, PGD?, and histamine. At any given dose, the treated groups also released less mediator (Fig. 3). The thresholds for both mediator release and sneezing required a pollen challenge dose in most treated patients higher than typically encountered in natural exposure. The 3.3 and 16.5 mg pollen challenges are probably in excess of natural exposure, but demonstrate that reactivity has not been completely ablated, at least by this dose of immunotherapy.‘4 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. Correlation of these challenge responses with immunologic responses still remains to be accomplished. A more complete view of the pathogenesis of allergic reactions emphasizes that there is more to clinical reactions than a transient release of short-acting mediators resulting in evanescent manifestations. IgE-
mediated allergic reactions are not necessarily immediate and short lived. In the skin, nasal passages, and lower airways, challenges often lead not only to immediate responses but to a subsequent “late-phase” reaction starting 3 to 11 hours after exposure, which may be quite prolonged.‘5 In the skin, IgE antibodies are clearly necessary to such a reaction, and recent evidence in the lung and the nose links these reactions to secondary release of many of the same mediators that appear in the immediate reaction. For instance, a nasal challenge study by Naclerio et al.“j shows a second wave of symptoms and mediator release 3 to 11 hours after the initial challenge. The mediators found include histamine, TAME-esterase, and kinins, but curiously PGD, is never found. The absence of PGD, raises the possibility of a different cellular source for the second wave of mediators, because a second challenge 11 hours after the first will, in contrast, result in the prompt appearance of PGD, along with the other mediators.‘j It seems likely that the late-phase reaction is just as important in the pathogenesis of allergic disease as the early reaction is. For example, asthma attacks are uncommonly immediate; rather, they take hours or days to develop, and clear up completely only after days or weeks of treatment. Nasal disease can show the same pattern. The late-phase allergic reactions takes on added dimension when it is realized that corticosteroids are more effective in ablating the late phase than the early phase.17 Furthermore, in a rabbit model, IgG antibodies protect more against the late than the early phase. la Most important to this discussion, several studies in humans indicate that immunotherapy changes the late-phase reaction to bronchial challenge more than it changes the immediate reaction.19, 2oInasmuch as the late phase may be partially inflammatory, it may be particularly important in the development of nonspecific reactivity, and thus immunotherapy could secondarily influence nonspecific reactivity favorably. In this way, recent evidence makes a somewhat different case for immunotherapy than is traditional, and indicates that bronchial hyperreactivity might be susceptible to improvement by proper management of allergic reactions. The effectiveness of immunotherapy in seasonal hay fever has been subjected to double-blind study for a number of allergens. Table I lists a number of studies that show the significance of the clinical results in grass, ragweed, mountain cedar, and birch pollen allergies. Only one study, by Fontana et a12’ failed to find significant relief, mainly because the study design rated patients as not improved if there were any symptoms at all. In general, patients undertaking immu-
VOIUME 8’ NUMBEH 5 PART 2
T NOIY Treated
Non Trtalcd A
Fig. 3. Absolute amount of mediator released over and treated (n = 12) (0) groups of patients. Statistical in mediator produced over baseline levels.
baseline levels for nontreated comparison
Frankland and Augustin” Lowell and Franklin
Fontana et al.*’
1954 Grass 1963 Mixed 1966 Ragweed
Norman et al.’ Lichtenstein et al.** Sadanet a1.26
1968 Ragweed 1968 Antigen E 1969 Ragweed
Lichtenstein et al.* Penceet aLz7 Viander and Koivikko’” Weyer et al.29
1971 1976 1976 1981
Duration of study
1 l-3 2 3-5 1 l-2 1
Ragweed Mountain cedar Birch Mixed grass
notberapy are not completely cured but have significantly less severe symptoms. In the usual allergies to external allergens, because demonstrable clinical relief is associated with mea-
1 1 1 1
in atlergic No.
fn =: 26) (*I
improved/total trested Sisnir&rwct
Adults Adults/children Children Children Adults Adults Children
Adults Adults Adults Adults
78199 20163 17.7:35 11.9/25
33 ‘99 9;59 15.7’35 11.7!26
14118 7:18 Of 18 treated patients. 13 had lower symptom scoresthan any of 17 control patients 7119 2121 13117 b/l5 32/38 11:19 Symptom-medication scoresbetter in 17 extract patients than in 16 placebo patients _l_ll
Kes Yes NO No Yes t/es Yes
Yes Yes Yes Yes
surable immunologic responses, materials (extracts j should contain the antigens required to incite these responses. Recent work with extracts of Alternaria and Cladosporium (two molds important in summer
J. ALLERGY CLIN. IMMUNOL. MAY 1988
and fall allergies) indicates that most, if not all, commercial extracts of these two species are seriously deficient in the proteins that induce the allergic response in patients.“. 23 Attempts at immunotherapy with these extracts may therefore be useless, and this example illustrates that the analogy created by study of a few well-defined allergenic extracts does not automatically extend to every extract of every allergen. Immunologic methods such as crossed immunoelectrophoresis and crossed radioimmunoelectrophoresis now allow accurate analysis of extracts and identification of allergenic proteins. Adoption of modern methods of immunologic standardization of extracts has been furthered by an international committee on standardization of allergens, and should improve the quality of extracts in the next few years so that the practitioner can have confidence that the available materials will produce the desired responses. Some commercial extracts of Alternaria and Cladosporium have already been improved by the use of better standardization techniques. REFERENCES 1. Norman PS, Winkenwerder WL. Immunotherapy of hay fever with ragweed antigen E: comparisons with whole pollen extract and placebos. J ALLERGY CLIN IMMLJNOL 1968;42:93-108. 2. Van Metre TE Jr, Adkinson NF Jr, Amodio FJ, et al. A comparative study of the effectiveness of the Rinkel method and the current standard method of immunotherapy for ragweed pollen hay fever. J ALLERGY CLIN IMMUNOL 1980;66:500-13. 3. Norman PS, Lichtenstein LM. The clinical and immunologic specificity of immunotherapy. J ALLERGY CLIN IMMUNOL 1978;61:370-7. 4. Lowell FC, Franklin W. A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever. N Engl J Med 1965;273:675-9. 5. Lichtenstein LM, Ishizaka K, Norman PS, Kagey-Sobotka A, Hill BM. IgE antibody measurements in ragweed hay fever: relationship to clinical severity and the results of immunotherapy. J Clin Invest 1973;52:472-82. 6. Platts-Mills TAE, von Maur RK, Ishizaka K, Norman PS, Lichtenstein LM. IgA and IgG anti-ragweed antibodies in nasal secretions. J Clin Invest 1976;57: 1041-50. 7. Rocklin RE, Sheffer AL, Greineder DK, Melmon KL. Generation of antigen-specific suppressor cells during allergy desensitization. N Engl J Med 1980;302:1213-9. 8. Lichtenstein LM, Norman PS, Winkenwerder WL. A single year of immunotherapy for ragweed hay fever: immunologic and clinical studies. Ann Intern Med 1971;75:663-71. 9. Creticos PS, Van Metre TE, Mardiney MR, Rosenberg GL, Norman PS, Adkinson NF Jr. Dose response of IgE and IgG antibodies during ragweed immunotherapy. J ALLERGY CLIN IMMUNOL 1984;73:94-104. 10. Naclerio RM, Meier HL, Kagey-Sobotka A, et al. Mediator release after nasal airway challenge with allergen. Am Rev Respir Dis 1983;128:597-602. 11. Proud D, Togias A, Naclerio RM, Crush SA, Norman PS, Lichtenstein LM. Kinins are generated in vivo following nasal
airway challenge of allergic individuals with allergen. J Clin Invest 1983;72:1678-85. Creticos PS, Peters SP, Adkinson NF Jr, et al. Peptide leukotriene release after antigen challenge in patients sensitive to ragweed. N Engl J Med 1984;310: 1626-30. Baumgarten CR, Togias AG, Naclerio RM, Lichtenstein LM, Norman PS, Proud D. Influx of kininogens into nasal secretions after antigen challenge of allergic individuals. J Clin Invest 1985;76:191-7. Creticos PS, Adkinson NF Jr, Kagey-Sobotka A, et al. Nasal challenge with ragweed pollen in hay fever patients: effect of immunotherapy. J Clin Invest 1985;76:2247-53. Herxheimer H. The late bronchial reaction in induced asthma. Int Arch Allergy Appl Immunol 1952;3:323. Naclerio RM, Proud D, Togias A, et al. Inflammatory mediators in late antigen-induced rhinitis. N Engl J Med 1985; 313:65-70. Pelikan Z. The effects of disodium cromoglycate and beclomethasone dipropionate on the late nasal mucosa response to allergen challenge. Ann Allergy 1982;49:200-12. Shampain MP, Behrens BL, Larsen GL, Henson PM. An animal model of late pulmonary responses to Alternaria challenge. Am Rev Respir Dis 1982;126:493-8. Metzger WJ, Donnelly BA, Richerson HB. Modification of late asthmatic responses (LAR) during immunotherapy for Alrernaria-induced asthma. J ALLERGY CLIN IMMUNOL 1983; 71:119. Warner JD, Price JF, Soothill JF, Hey EN. Controlled trial of hyposensitization to Dermatophagoides pteronyssinus in children with asthma. Lancet 1978;2:912. Fontana VJ, Holt LE Jr, Mainland D. Effectiveness of hyposensitization therapy in ragweed hay-fever in children. JAMA 1966;195:985-92. Yunginger JW, Jones RT, Nesheim ME, Geller M. Studies on Alternaria allergens. III. Isolation of a major allergenic fraction (Alt-l). J ALLERGY CLIN IMMUNOL 1980;66:138. Aukrust L, Borch SM. Partial purification and characterization of two Cludosporium herbarum allergens. Int Arch Allergy Appl Immunol 1979;60:68. Frankland 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;1:1055-7. Lichtenstein LM, Norman PS, Winkenwerder WL. Clinical and in vitro studies on the role of immunotherapy in ragweed hay fever. Am J Med 1968;44:514-24. Sadan 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;280:623-7. Pence HL, Mitchell DQ, Greely RL, Updegraff BR, Selfridge HA. Immunotherapy for mountain cedar pollinosis: a doubleblind controlled study. J ALLERGY CLIN IMMUNOL 1976;58: 39-50. Viander M, Koivikko A. The seasonal symptoms of hyposensitized and untreated hay fever patients in relation to birch pollen counts; correlations with nasal sensitivity, prick tests and RAST. Clin Allergy 1976;8:387-96. Weyer A, Donat N, L’Heritier C, et al. Grass pollen hyposensitization versus placebo therapy II. Clinical effectiveness and methodological aspects of a preseasonal course of desensitization with a four-grass pollen extract. Allergy 198 1;36: 309-17.