Immunologic changes produced by immunotherapy

Considerable information has been published concerning the immunologic mechanisms involved in the symptom improvement produced by immunotherapy. Most of the information is found in the subcutaneous immunotherapy literature, but data about the changes produced by SLIT are becoming more abundant.

Change in serum antibody levels is one of the most common parameters measured when investigating the effect of immunotherapy on the immune system. One of the first measurable changes with immunotherapy is an increase in allergen-specific IgG. Allergen-specific IgG antibodies are believed to contribute to the improvement seen with immunotherapy by acting as “blocking antibodies,” preventing allergens from binding to IgE located on the surfaces of mass cells and basophils. By interfering with allergen cross-binding of two adjacent surface IgE molecules, IgG prevents transmembrane signal transduction, and subsequently degranulation of the mast cell or basophil is averted . The different subsets of IgG antibodies respond differently during the course of immunotherapy. The predominant subset to increase early in the course of immunotherapy is IgG1. Its serum levels typically increase quickly in the first few months of immunotherapy, but then the levels tend to slowly decrease as treatment is continued. Increases in the level of IgG4 are not seen until later in the course of treatment, but the levels remained elevated throughout the remainder of immunotherapy and persist for several years after its discontinuation . In addition to serving as blocking antibodies, IgG has also been found to inhibit the process of serum-facilitated antigen presentation. Serum-facilitated antigen presentation is a process that allows IgE-mediated presentation of allergens to allergen-presenting cells at very low serum concentrations. By the action of IgG blocking this process, a much higher concentration of allergen is necessary to induce T lymphocyte proliferation and pro-allergic cytokine release .

Allergen-specific IgE levels typically increase by at least twofold in the serum within the first few months of immunotherapy. Over the next 2 years, the levels of allergen-specific IgE typically decline and eventually fall below pretreatment levels . Because allergic rhinitis and atopic asthma are believed to be mediated by the presence of an abnormal amount of allergen-specific IgE, it would stand to reason that the level of IgE present in the serum would correlate with symptom changes during immunotherapy. No such correlation with the decline in serum IgE and decrease in symptom levels has been shown, however . Successful immunotherapy has also been shown to blunt the typical post–allergy season increase in allergen-specific IgE .

Although most attention has been focused on changes in IgE and IgG, other immunoglobulin changes have been reported. It is believed that immunotherapy can stimulate B lymphocytes to increase IgA and IgM production. This increase could boost the barrier function against antigen penetration at mucosal surfaces. An increase in allergen-specific IgA in nasal secretions has been detected during the course of immunotherapy . More recently, the increase in IgA was found to be specific to IgA2. The increase in IgA2 correlated with an increase in nasal TGFβ expression and induction of monocyte IL-10 expression. These changes have been associated with development of tolerance in allergic patients .

Evidence suggests that T lymphocytes play a major role in mediating the allergic inflammatory response . There seem to be different subsets of T cells defined by the types of cytokines they produce. Th1 cells produce cytokines, such as interferon (INF)-gamma, interleukin (IL)-2, and tumor necrosis factor (TNF)-β, that induce phagocytic and T-cell–mediated microbial defense reactions. Th2 cells produce cytokines that promote IgE-mediated hypersensitivity responses. The original Th2 cytokines identified included IL-4, IL-5, IL-6, and IL-13 . The ratio of Th1 to Th2 cells is believed to be an important factor in allergy development. Individuals who have a higher ratio of Th2 lymphocytes are more prone to develop allergic manifestations. Individuals shifted to a more Th1-dominant lymphocyte profile are believed to have a lesser propensity for allergic disease. Immunotherapy has consistently been shown to increase the ratio of Th1 cells relative to Th2, but the absolute change in specific cytokines causing this ratio change is variable. Immunotherapy has also been shown to result in an increase in the number of allergen-specific suppressor T cells, which may be attributable to an alteration in T-cell receptor types. T lymphocyte production of IL-10 has also been reported to be an important component of successful immunotherapy. Much more is being discovered about the central role of T cells in successful immunotherapy .

Most of the basic science research about the immunologic changes produced by immunotherapy has been done with injection immunotherapy. As SLIT has become a more popular option of antigen delivery, more research is becoming available about the immunologic changes produced with this delivery technique. Box 1 lists many of the immunologic parameter changes that have been demonstrated with SLIT.

Many other immune system changes have been demonstrated with immunotherapy, although the major changes have been listed above. It is beyond the scope of this publication to explore more deeply the vast amount of research surrounding immunologic changes produced by immunotherapy. Nonetheless, an understanding of these changes is important, not only for a better understanding of how to manage immunotherapy in clinical practice but also in developing better ways to treat allergic disease with immunotherapy and other medications in the future.

Efficacy of injection immunotherapy for allergic rhinitis

The efficacy of subcutaneous injection immunotherapy has been demonstrated through multiple studies. A recent Cochrane Systematic Review has been published containing a comprehensive review of quality clinical trials concerning the efficacy of subcutaneous immunotherapy for seasonal allergy using standardized allergens . The review included 51 studies that met strict inclusion criteria. The combined total of participants was 1645 receiving active immunotherapy and 1226 receiving placebo. Only 15 of the studies (active immunotherapy subjects n = 597 and placebo subjects n = 466) included enough data to allow meta-analysis of symptom reduction scores. The meta-analysis revealed an overall significant reduction in symptom scores when combining the data of these 15 studies. The combined standardized mean difference (SMD) for symptom scores after completion of subcutaneous immunotherapy was −0.73 (95% CI, −0.97 to −0.50, P <.00001). The SMD is a statistic that expresses the difference in means between immunotherapy and control groups in units of the pooled standard deviation. An SMD score less than zero indicates a positive effect. Medication use information was sufficient in 13 studies to allow inclusion in the meta-analysis (active immunotherapy participants n = 549 and placebo participants n = 414). A significant reduction in medication scores was demonstrated in the combined results of the 13 studies. The SMD for medication scores following immunotherapy was −0.57 (95% CI, −0.82 to −0.33, P <.00001). An analysis of combined symptom and medication scores was performed on 8 studies (active immunotherapy subjects n = 320 and placebo subjects n = 297), revealing a significant reduction in combined symptom and medication scores. The combined SMD for medication and symptom scores following subcutaneous immunotherapy was −0.48 (95% CI, −0.67 to −0.29, P <.00001).

In the systematic review by Calderon and colleagues , an analysis was also performed for nasal, bronchial, and ocular symptom scores individually. Nine studies allowed for analysis of nasal symptom scores (active immunotherapy subjects n = 396 and placebo subjects n = 276). The data indicated a significant reduction in nasal symptom scores after active immunotherapy. The combined SMD for nasal symptom scores following subcutaneous immunotherapy was −1.59 (95% CI, −2.29 to −0.89, P <.00001). Because of the way data were reported in the published studies, only three studies met inclusion criteria for analysis of ocular symptom scores (active immunotherapy subjects n = 226 and placebo subjects n = 119). A significant reduction in ocular symptom scores was seen in the active treatment group. The combined SMD for ocular symptom scores following immunotherapy was −1.80 (95% CI, −3.28 to −0.31) ( P <.02).

Rhinoconjunctivitis quality-of-life measurement instruments are often used to assess improvement in patients undergoing intervention for allergies. Five studies (active immunotherapy subjects n = 332 and placebo subjects n = 239) in the systematic review allowed for rhinoconjunctivitis quality-of-life meta-analysis . The meta-analysis revealed clinically and statistically significant reductions in the rhinoconjunctivitis quality-of-life measures. The combined SMD for rhinoconjunctivitis quality of life following subcutaneous immunotherapy was −0.52 (95% CI, −0.69 to −0.34, P <.00001).

The systematic review by Calderon and colleagues is significant in that it reaffirms the widely accepted belief that allergen-specific immunotherapy can result in significant improvements in symptom scores and medication use for allergic nasal, bronchial, and ocular manifestations. The authors astutely pointed out that some caution needs to be taken in evaluating these findings, because there is such heterogeneity within allergy clinical trial publications. No pediatric studies met the qualifications to enter into the systematic review, so no assumptions can be made on the effectiveness of immunotherapy in this population. The review also only included seasonal allergic rhinitis, so it does not address the question of the efficacy of injection immunotherapy for the treatment of perennial allergic rhinitis.

Another comprehensive review of the efficacy of injection immunotherapy was recently published as an update to the Allergic Rhinitis and Its Impact on Asthma (ARIA) publication . This update to the original ARIA document was intended to review data on the safety and efficacy of specific immunotherapy. Like in the Calderon review, the authors of the ARIA update concluded that injection immunotherapy for inhalant allergens is effective for seasonal allergic rhinitis. The ARIA update also evaluated the effectiveness of injection immunotherapy for perennial allergens, particularly dust mites. A review of six publications evaluating specific immunotherapy for dust mites was included and confirmed the clinical efficacy of immunotherapy for this antigen.

Efficacy of injection immunotherapy for allergic rhinitis

The efficacy of subcutaneous injection immunotherapy has been demonstrated through multiple studies. A recent Cochrane Systematic Review has been published containing a comprehensive review of quality clinical trials concerning the efficacy of subcutaneous immunotherapy for seasonal allergy using standardized allergens . The review included 51 studies that met strict inclusion criteria. The combined total of participants was 1645 receiving active immunotherapy and 1226 receiving placebo. Only 15 of the studies (active immunotherapy subjects n = 597 and placebo subjects n = 466) included enough data to allow meta-analysis of symptom reduction scores. The meta-analysis revealed an overall significant reduction in symptom scores when combining the data of these 15 studies. The combined standardized mean difference (SMD) for symptom scores after completion of subcutaneous immunotherapy was −0.73 (95% CI, −0.97 to −0.50, P <.00001). The SMD is a statistic that expresses the difference in means between immunotherapy and control groups in units of the pooled standard deviation. An SMD score less than zero indicates a positive effect. Medication use information was sufficient in 13 studies to allow inclusion in the meta-analysis (active immunotherapy participants n = 549 and placebo participants n = 414). A significant reduction in medication scores was demonstrated in the combined results of the 13 studies. The SMD for medication scores following immunotherapy was −0.57 (95% CI, −0.82 to −0.33, P <.00001). An analysis of combined symptom and medication scores was performed on 8 studies (active immunotherapy subjects n = 320 and placebo subjects n = 297), revealing a significant reduction in combined symptom and medication scores. The combined SMD for medication and symptom scores following subcutaneous immunotherapy was −0.48 (95% CI, −0.67 to −0.29, P <.00001).

In the systematic review by Calderon and colleagues , an analysis was also performed for nasal, bronchial, and ocular symptom scores individually. Nine studies allowed for analysis of nasal symptom scores (active immunotherapy subjects n = 396 and placebo subjects n = 276). The data indicated a significant reduction in nasal symptom scores after active immunotherapy. The combined SMD for nasal symptom scores following subcutaneous immunotherapy was −1.59 (95% CI, −2.29 to −0.89, P <.00001). Because of the way data were reported in the published studies, only three studies met inclusion criteria for analysis of ocular symptom scores (active immunotherapy subjects n = 226 and placebo subjects n = 119). A significant reduction in ocular symptom scores was seen in the active treatment group. The combined SMD for ocular symptom scores following immunotherapy was −1.80 (95% CI, −3.28 to −0.31) ( P <.02).

Rhinoconjunctivitis quality-of-life measurement instruments are often used to assess improvement in patients undergoing intervention for allergies. Five studies (active immunotherapy subjects n = 332 and placebo subjects n = 239) in the systematic review allowed for rhinoconjunctivitis quality-of-life meta-analysis . The meta-analysis revealed clinically and statistically significant reductions in the rhinoconjunctivitis quality-of-life measures. The combined SMD for rhinoconjunctivitis quality of life following subcutaneous immunotherapy was −0.52 (95% CI, −0.69 to −0.34, P <.00001).

The systematic review by Calderon and colleagues is significant in that it reaffirms the widely accepted belief that allergen-specific immunotherapy can result in significant improvements in symptom scores and medication use for allergic nasal, bronchial, and ocular manifestations. The authors astutely pointed out that some caution needs to be taken in evaluating these findings, because there is such heterogeneity within allergy clinical trial publications. No pediatric studies met the qualifications to enter into the systematic review, so no assumptions can be made on the effectiveness of immunotherapy in this population. The review also only included seasonal allergic rhinitis, so it does not address the question of the efficacy of injection immunotherapy for the treatment of perennial allergic rhinitis.

Another comprehensive review of the efficacy of injection immunotherapy was recently published as an update to the Allergic Rhinitis and Its Impact on Asthma (ARIA) publication . This update to the original ARIA document was intended to review data on the safety and efficacy of specific immunotherapy. Like in the Calderon review, the authors of the ARIA update concluded that injection immunotherapy for inhalant allergens is effective for seasonal allergic rhinitis. The ARIA update also evaluated the effectiveness of injection immunotherapy for perennial allergens, particularly dust mites. A review of six publications evaluating specific immunotherapy for dust mites was included and confirmed the clinical efficacy of immunotherapy for this antigen.

Efficacy of injection immunotherapy for asthma

The clinical efficacy of specific immunotherapy in the treatment of asthma was reviewed in a recent meta-analysis found in the Cochrane Library . The authors reviewed changes in symptom and medication scores for multiple antigens individually. The meta-analysis revealed significant symptom score reduction for immunotherapy using dust mite and pollen. There was no significant improvement following immunotherapy with cat, dog, or multiple allergen extracts. When all allergens were combined, there was not a significant reduction in symptom scores, although the authors recognize there was significant heterogeneity between studies. There was a significant decrease in medication use scores for all allergens combined. Analysis of medication scores for individual allergens was not included. Analysis of lung function change revealed no significant difference in FEV ₁ or peak expiratory flow. A small reduction in nonspecific bronchial hyperreactivity following immunotherapy was demonstrated. Nonspecific bronchial hyperreactivity was evaluated by bronchial challenge with nonspecific agents, such as methacholine, histamine, or acetylcholine. Allergen-specific bronchial hyperreactivity was significantly reduced when analyzing all allergens combined. The improvement was most striking for mite immunotherapy. Pollen and dander immunotherapy also showed significant improvement in allergen-specific bronchial hyperreactivity. The authors of the meta-analysis concluded that allergen-specific immunotherapy was effective in reducing allergy symptom and use of asthma medications.

The meta-analysis by Calderon and colleagues included five studies reporting data for bronchial symptom score analysis (active immunotherapy subjects n = 266 and placebo subjects n = 163). The review revealed a significant reduction in bronchial symptom scores favoring the active treatment group. The combined SMD for bronchial symptom scores following immunotherapy was −0.59 (95% CI, −1.06 to −0.11, P = .02) .