Allergen Immunotherapy and Tolerance

Abstract

Successful allergen-specific immunotherapy (AIT) is associated with a marked decrease in symptoms on allergen exposure, a reduced requirement for 'rescue' anti-allergic drugs and improvement in patients' quality of life. These benefits persist for at least several years following discontinuation of immunotherapy - the hallmark of clinical and immunological tolerance. AIT has been shown to modulate both innate and adaptive immunological responses. Early suppression of innate effector cells of allergic inflammation (mast cells, basophils), regulation of pro-allergic T helper 2 type (Th 2) responses and IgE+ B cell responses have been shown to occur both in the tissue and in the peripheral blood during AIT. The allergen-tolerant state is associated with local and systemic induction of distinct populations of allergen-specific T regulatory cells including IL-10+ Tregs (Tr1 cells), TGF-β+ Tregs and FoxP3+ memory T regs. B cells are switched in favour of producing IgG (particularly IgG4) antibodies and associated blocking activity for IgE-dependent events, including basophil activation and IgE-facilitated allergen binding to B cells. An induction of IL-10+ B regulatory cells and alterations in dendritic cell subsets have also recently been described. These events are followed by the induction of T regulatory cells, suppression of allergen-specific T cell proliferation and immune deviation from Th2 in favour of Th1 responses. Alternative mechanisms of tolerance include apoptosis/deletion of antigen-specific memory Th2 cells and/or a failure of co-stimulation leading to T cell anergy.

Subcutaneous immunotherapy with purified Der p1 and 2 suppresses type 2 immunity in a murine asthma model

“…Clinical efficacy of SIT is associated with the neutralizing capacity of the spIgGs,4 while symptom score in allergic asthma is inversely correlated to the ratio of spIgG over spIgE,22 indicating the relevance of IgG response induced during SIT. Therefore, we calculated the changes in the ratio of Der p1‐spIgG1 over Der p1‐spIgE and compared between groups (Figure 2F).…”

“…Specific immunotherapy (SIT) has been shown to induce durable immunological changes in response to the allergen, through generating neutralizing antibodies, through suppressing numbers and activity of allergen‐specific Th2 cells and type 2 innate lymphoid cells (ILC2s), and by inducing regulatory T‐cell activity 2. Successful SIT has been associated with enhanced release of IL‐10 in PBMC cultures restimulated with allergen,3 serum‐dependent suppression of cross‐presentation by B cells,4 and selective loss of those T‐cell clones with allergen‐epitope specificities that are increased in atopic individuals compared to healthy controls 5, 6. Specific immunotherapy (SIT) induces long‐term tolerance to the allergen, as evidenced by the absence of allergic manifestations upon repeated allergen challenges 1…”

Harnessing Nanoparticles for Immune Modulation

“…Whether the intramuscular fluid liposome-antigen combination induced peripheral immune tolerance was not tested, but intraperitoneal (IP) administration of fluid OVA-decorated liposomes can induce antigen-specific IgE non-responsiveness [31,32]. While this was argued to occur in a T cell-independent fashion, the increased levels of IgG after IP administration suggest immune deviation [33]. Notwith-standing this, these findings highlight the importance of understanding the contribution of fluidity and stiffness in NPmediated manipulation of immune outcomes.…”

The Frequency and Intensity of Bronchial Hyper-Reactivity in Patients with Allergic Asthma on Immunotherapy

“…The switch of cytokine profile to a primary IL-2 and IFN-γ response results in inhibition of the IL-4 dependent IgE production, reinforced by a decrease in the production of IL-4 from Th2 cells. Secondly, the activity of mast cells is reduced because of a lack of IL-3 dependent activation, a reduced local production of IgE, and a decreased production of histamine-releasing factors [5,6]. A cytokine-independent decrease in mediator release from mast cells could concurrently be present, as well as a switch from IgE+ to IgE-phenotype [5].…”

“…Secondly, the activity of mast cells is reduced because of a lack of IL-3 dependent activation, a reduced local production of IgE, and a decreased production of histamine-releasing factors [5,6]. A cytokine-independent decrease in mediator release from mast cells could concurrently be present, as well as a switch from IgE+ to IgE-phenotype [5]. The decreased activity of mast cells results in a decreased release of allergic mediators, thereby diminishing vascular permeability, smooth-muscle contraction, and the activity of chemotactic factors such as PAF and eosinophil chemotactic activity [7][8][9][10][11].…”