Page 1268 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1228 Part tEN Prevention and Therapy of Immunological Diseases

MECHANISMS OF SIT specific immunoglobulin G (IgG) antibodies, which increase
progressively during treatment. This led to suggestions that SIT
might work by inducing antibodies that intercept the allergen
KEY CONCEPtS and “block” the allergic response. In patients treated for venom
anaphylaxis, the development of allergen-specific IgG antibody
Possible Mechanisms of Immunotherapy correlates with clinical efficacy, but for other allergens, the
magnitude of the IgG response is not closely related to the degree
• Induction of immunoglobulin G (IgG) (blocking) antibodies of efficacy. Moreover, the rise in IgG follows, rather than precedes,
• Reduction in specific IgE (long-term)
• Reduced recruitment of effector cells onset of clinical benefit. Allergen-specific IgE antibodies increase
3
• Altered T-cell cytokine balance (shift to T-helper cell-1 [Th1] from Th2) initially, but the usual seasonal rise in IgE is blunted. Over several
• T-cell anergy years, the amount of allergen-specific IgE declines but does not
• B-cell suppression disappear. In keeping with this, there is little effect on immediate
skin test responses to allergen. In contrast, the late-phase skin
test response is virtually abolished after successful SIT. Similar
patterns are observed for late-phase nasal and airway responses. 4
The primary reason for studying the mechanisms of SIT is to SIT also affects allergen-specific T cells. In both skin and the
identify features that are biologically important and thus to devise nose, successful SIT is accompanied by a reduction in T-cell
new forms of immunotherapy that may improve efficacy, increase and eosinophil recruitment in response to allergen challenge. In
safety margins, shorten treatment courses, or achieve more durable parallel, the balance of T-helper cell-1 (Th1) and Th2 cytokine
results from SIT. At least three distinct phases can be identified expression (Chapter 16) alters at allergen-challenged sites. Th2
2
in SIT, each with distinct immunological mechanisms. Initially, cytokine expression is not affected, but an increased proportion
there is pharmacological desensitization, in which basophils and of the recruited T cells express the Th1 cytokines interleukin-2
mast cells are rendered tolerant of the allergen. This is achieved (IL-2), interferon-γ (IFN-γ), and IL-12. In addition, there is induc-
quickly, within a few days if the rush protocol is followed. Clini- tion of allergen-specific CD4 Tregs that express CD25, FOXP3,
2
cally, this not only allows the patient to tolerate the maintenance and IL-10. IL-10 is induced within a few days of starting SIT
dose of allergen but also protects against acute exposure to allergen and has a number of biological effects that could explain the
(e.g., a wasp sting). This state of pharmacological tolerance is beneficial effects of immunotherapy. These include modulation of
not permanent and rapidly disappears if SIT is stopped. During IL-4–induced B-cell IgE production in favor of IgG4, inhibition of
the first year of maintenance SIT, T-cell tolerance is achieved, IgE-dependent mast cell activation, inhibition of human eosino-
with abrogation of late-phase responses to allergen exposure phil cytokine production and survival, suppression of IL-5, and
and induction of regulatory T cells (Tregs). Finally, with prolonged induction of antigen-specific anergy (Fig. 91.1). Taken together,
treatment, B-cell tolerance develops, and the level of sensitizing these findings suggest that SIT modulates allergen-specific T
antibodies decreases. cells, which explains why clinical and late-phase responses are
Following subcutaneous injection of allergen extracts, a small attenuated without much effect on allergen-specific antibody
proportion of the allergenic material is taken up by phagocytic levels. Further work in this area is now concentrating on finding
cells and carried to regional lymph nodes. The process is fairly more efficient ways of inducing allergen-specific Tregs. Some
inefficient: <1% of a radiolabeled dose actually reaches the lymph caution is needed: Most of the evidence of Treg induction is from
nodes. Almost all studies have shown that SIT induces allergen- peripheral blood rather than from target organs, and although

Allergen immunotherapy Degranulation of mast cells

- IL-4
Th2 IL-13 Th2 B cell IgE
+
IL-5 Eosinophil
-
+
Th0 Allergic mucosal
inflammation -
- and symptoms
Th1 IL-12, αIFN
-
+ IgG, IgA, blocking Ab’s
T cell ‘anergy’

IL-10
Tr cells TGF-β Th2 B cell

-
FIG 91.1 Immunological mechanisms of specific immunotherapy.