IL-5 production by allergen-stimulated T cells following grass pollen immunotherapy for seasonal allergic rhinitis

Abstract

SUMMARYGrass pollen immunotherapy for the treatment of seasonal allergic rhinitis ('summer hayfever') results in improvement in symptoms, a reduction in the early and late phase responses to allergen provocation and decreased tissue eosinophilia. Immunotherapy may act by altering the pattern of cytokine production by allergen-specific T cells from a 'Th2-type' (IL-4 and IL-5) profile to a 'Th1-type' (interferon-gamma (IFN-g)) profile. We set out to determine whether clinical improvement following specific allergen immunotherapy is accompanied by reduced production of the pro-eosinophilic and archetypal 'Th2-type' cytokine, IL-5. Peripheral blood mononuclear cells (PBMC) were isolated from (i) 13 patients who had received 6 or 7 years' continuous conventional immunotherapy with timothy grass pollen (Phleum pratense); (ii) 14 patients who had received 3 or 4 years of conventional immunotherapy followed by 3 years of placebo treatment; (iii) 12 matched seasonal rhinitic patients who had never received immunotherapy; and (iv) 17 non-atopic normal controls. PBMC were stimulated with 20 mg/ml and 200 mg/ml P. pratense extract, or 10 mg/ml of Mycobacterium tuberculosis purified protein derivative (PPD), at 2 × 10 6 cells/ml and 5 × 10 6 cells/ml. IL-5 concentrations in culture supernatants collected after 6 days' culture were measured by ELISA. IL-5 production in response to stimulation with P. pratense extract was highly reproducible and was elevated in both of the immunotherapy treated groups and the untreated rhinitics relative to non-atopic controls (P < 0 . 005 for each group relative to non-atopic controls, under each of the four conditions tested). However, no significant reduction was observed in IL-5 production when immunotherapy treated patients were compared with untreated rhinitic controls. Moreover, abrogation of the cutaneous late-phase responses to allergen following treatment was not associated with reduced IL-5 production by allergen-stimulated peripheral blood T cells. Reduced IL-5 production by peripheral blood T cells may not be necessary for immunotherapy to be effective. Local immunodulation of T cell responses may play a role in this form of treatment.

Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1 : Th2 cytokine ratios

“…Other investigators have reported a decrease in Th2 cytokine production in favour of Th1 cytokines such as IFN‐γ by peripheral blood T cells in response to allergen 30 . In contrast, our own cross‐sectional studies did not identify a significant difference in peripheral T‐cell responsiveness to allergen or IL‐5 production in patients who had received immunotherapy compared to placebo‐treated patients 31 . In the present study we performed a further prospective randomized controlled trial of grass pollen immunotherapy in patients with severe hayfever.…”

“…In addition to the findings reported here, a number of other studies have reported a lack of effect of clinically successful pollen immunotherapy on peripheral blood T‐cell responses 35–37 . Our own cross‐sectional studies of peripheral blood T‐cell responses after 4–7 years of clinically effective immunotherapy 38 did not show any evidence for reduction in grass pollen‐induced proliferation or IL‐5 production 31 . This is unlikely to be explained by methodological differences since using identical methodology previously we demonstrated a close correlation between in vitro cytokine production for IL‐5 in PBMC cultures and the clinical severity of allergic disease expression 15 .…”

T cell responses induced by allergen-specific immunotherapy

“…At the beginning of the 1990s, with the definition of the Th1–Th2 paradigm, initial results based on several in vitro and in vivo models concluded that SCIT skewed allergen‐specific responses from Th2 to a more protective Th1 phenotype, a mechanism known as immunodeviation [9,40]. Others have been unable to reproduce these findings, and reported no changes in proliferative responses or cytokine production [41], due probably to variations of SCIT regimens and in vitro methodology. Nevertheless, Th1‐redirection induced by SCIT with allergen extracts or peptides continues to be reported in more recent studies [42–44].…”

Cytokines: Principles and prospects

“…Immunotherapy to divert the T cell cytokine response from a type 2 to a type 1 profile should therefore prevent the allergic response to antigen. A number of studies have found that conventional allergen immunotherapy causes a reduction in T cell synthesis of IL‐4, but effects on type 1 and other type 2 cytokines are variable and the underlying mechanisms are not understood 190 , 191 , 192 …”