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Local respiratory allergy (LRA) is defined by the negativity of atopy tests, a clinical history suggestive of airway allergy and a positive response to the nasal and/or bronchial allergen challenge. The clinical spectrum of LRA is comprised of three conditions: local allergic rhinitis (LAR) and local allergic asthma in non-atopic patients, and dual allergic rhinitis (coexistence of allergic rhinitis and LAR) in atopic individuals. LRA is an independent disease phenotype not progressing to atopy over time, but naturally evolving to the clinical worsening and the onset of comorbidities. Published data suggests that LRA is mediated through the mucosal synthesis of allergen-specific (s)IgE, which binds to FcϵRI on resident mast cells, and in >50% of cases traffics to the blood stream to sensitize circulating basophils. To date, 4 clinical trials have demonstrated the capacity of allergen immunotherapy (AIT) to decrease nasal, conjunctival and bronchial symptoms, to improve quality of life, to increase the threshold dose of allergen eliciting respiratory symptoms, and to induce serum sIgG4 in LRA individuals. Collectively, these data indicate that local allergy is a relevant disease mechanisms in both atopic and non-atopic patients with airway diseases.

Rationale: rfhSP-D has been shown to suppress house dust mite and Aspergillus 74 fumigatus-induced allergic inflammation in murine models. 75 Objectives: We sought to elucidate the effect of rfhSP-D on FcεRI and CD23- 76 mediated grass pollen induced allergic inflammatory responses. 77 Methods: rfhSP-D, containing homotrimeric neck and lectin domains, was 78 expressed in Escherichia coli BL21 (λDE3) pLysS. PBMCs and sera were obtained 79 from grass pollen allergic individuals (n=27). The effect of rfhSP-D on basophil 80 activation and histamine release was measured by flow cytometry. IgE-facilitated 81 allergen binding and presentation was assessed by flow cytometry. Th2 cytokines 82 were measured in cell culture supernatants. The effect of rfhSP-D on IgE production 83 by B cells when stimulated with CD40L, IL-4 and IL-21 was also determined. 84 Results: rfhSP-D bound to Phleum pratense in a dose- and calcium-dependent 85 manner. Allergen-induced basophil responsiveness and histamine release was 86 inhibited in the presence of rfhSP-D, as measured by CD63, CD203c 87 (P=0.0086,P=0.04205), and intracellular-labelled DAO (P=0.0003,P=0.0148). The 88 binding of allergen-IgE complexes to B cells was reduced by 51%(P=0.002) in the 89 presence of rfhSP-D. This decrease was concomitant with reduction in CD23 90 expression on B cells (P

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SUMMARY Neonatal B cells have been considered immature because of their impaired capacity to produce immunoglobulins in response to polyclonal activators in vitro. Here we demonstrate that cord blood mononuclear cells (MNC) produce normal levels of IgE in vitro when cultured in the presence of interleukin-4 (IL-4), indicating that the B cells are mature in their capacity to switch to IgE-producing cells. However, in contrast to adult peripheral blood T cells, cord blood T cells failed to produce detectable levels of IL-4 upon activation by phytohaemagglutinin (PHA) concanavalin A (Con A) or combinations of PHA and the phorbol ester TPA. Interferon-gamma (IFN-γ) production by cord blood T cells following activation by Con A or PHA was also strongly reduced. However, high levels of IFN-γ, significantly higher than those produced by adult T cells, were synthesized in response to combinations of PHA and TPA, indicating that IFN-γ production by cord blood T cells is not intrinsically defective. In contrast, cord blood T cells produced levels of IL-2 that were significantly higher than those obtained by adult T cells tested in parallel. Collectively, our data indicate that the minimal levels of IgE production measured in cord blood (< 1 U/ml) are not due to immaturity of the cord blood B cells, but may be associated with the failure of cord blood T cells to produce detectable levels of IL-4, which has been shown to be responsible for induction of IgE synthesis both in vitro and in vivo.

Interleukin-4 (IL-4) is produced by T-helper cells type 2 (TH2) and induces IgE synthesis. T-helper cells type 1 (TH1) produce interferon-gamma (IFN-gamma) which suppresses TH2 and reduces IL-4 induced IgE production. In this :;tudy , we demonstrated that the levels of specific IgE in the serum of atopic children (n=20) were elevated while IL-4 production was increased and IFN-gamma secretion was reduced, compared to those of control group. Inter!eukin-4-induced IgE synthesis by peripheral blood mononuclear cells of atopic children in vitro was blocked in the presence of IFN-gamma. In addition, levels of soluble CD23-which is specifically induced by IL-4 were significantly elevated in our atopic patients. The data indicate that enhanced production of IL-4 and lowered IFN-gamma secretion by T-helper cells correlate with the elevated specific IgE levels in the serum of atopic children.

Allergen-specific Th2 cells from atopic individuals generally belong to the T helper 2 (Th2) subset producing, among other cytokines, high levels of IL-4, IL-5 and IL-13, but low levels of IL-2 and IFN-γ following activation. Both IL-4 and IL-13 induce IgE synthesis, which is inhibited by IFN-γ. IL-4, but not IL-13, also directs differentiation of naive CD4 + T cells into Th2 cells. Furthermore, IL-5 induces the differentiation of eosinophils and eosinophilia, whereas IL-3, IL-4 and IL-10 produced by Th2 cells, synergize with c-kit ligand in promoting mast cell growth. These observations indicate that allergy is a Th2 cell disease, and that targeting of allergen-specific Th2 cells may provide an efficient way to intervene in allergic inflammation. Three different approaches aimed at inhibiting the function or differentiation of allergen-specific Th2 cells are discussed. It is shown that an IL-4R and IL-13R antagonist inhibits IL-4-driven Th2 cell differentiation and human IgE production both in vitro and in SCID-hu mice. In addition, it is discussed that allergen-specific Th2 cells can be rendered anergic following stimulation with allergen-derived peptides, representing T cell activation inducing epitopes. These anergic Th2 cells fail to produce IL-4, IL-5 and IL-13, to proliferate, and to provide help to B cells for IgE synthesis after rechallenge with allergen- and antigen-presenting cells. Finally, it is shown that IL-4-driven allergen-specific Th2 cell differentiation can be redirected into a Th0 and Thl cell differentiation pathway by stimulating these IL-4-driven allergen-specific Th cell populations in the presence of IL-12, or by co-stimulating these cells via a novel T cell receptor, designated signalling lymphocyte activation molecule (SLAM). The clinical implications of these approaches are discussed.

SUMMARYInterleukin-4 (IL-4) has been shown to induce IgE synthesis by peripheral blood mononuclear cells (PBMC) of normal donors in vitro. However, induction of PBMC of patients with common variable immunodeficiency (CVI) with IL-4 resulted in IgE production in only two out of eight cases tested. PBMC of the first patient that produced IgE in response to IL-4 also secreted normal levels of IL-4 upon activation. PBMC of the second patient secreted very low levels of IL-4 in vitro which may account for the very low serum IgE levels in this patient. Of the other six patients who had very low serum IgE levels and whose PBMC failed to produce IgE in response to IL-4 in vitro, five did not secrete IL-4 upon in vitro activation. The capacity of the T cells to produce IL-4 was intact in the sixth patient. Collectively our data indicate the PBMC of the majority of patients with CVI are defective since they failed to respond appropriately to IL-4 and they failed to produce IL-4, contributing to the view that CVI is a heterogeneous disorder in which a variety of T and B cell defects occur.