T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction.

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-ß. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-ß-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.

Histamine induces Th2 activation through the histamine receptor 1 in house dust mite rhinitic but not asthmatic patients.

BACKGROUND: Effects of mast cell-released histamine on smooth muscle and endothelial cells are considered as responsible of immediate symptoms of anaphylaxis. However, little is known about histamine effects on Th2 lymphocytes, which orchestrate the allergic reaction upstream of mast cells. OBJECTIVE: We addressed this question in house dust mite (HDM) allergics, according to the presence of rhinitis or asthma and allergen stimulation. METHODS: Peripheral blood mononuclear cell from 15 rhinitic and 14 asthmatic HDM-allergic subjects and 16 controls were cultured with Der p 1 or histamine. The effect of Der p 1 on histamine receptor (H1R and H2R) expression was studied. T-cell cytokine production was studied upon Der p 1 or histamine stimulation. The role of H1R in histamine effects was assessed with levocetirizine. RESULTS: H1R and H2R are overexpressed on T cells from asthmatic but not from rhinitic subjects. Der p 1 increases H1R expression on CD4(+) cells from both allergic groups, and decreases it in controls, on CD4(+) and CD8(+) subsets. Der p 1 decreases T-cell H2R expression in asthmatics. Allergen increases IL-4 and IL-13 in both allergic groups. Histamine increases Th2 cytokines in rhinitics only, and levocetirizine abolishes this effect. In asthmatics and controls, histamine decreases T-cell cytokines through a non-H1R dependent pathway. CONCLUSION: In rhinitis but not in asthma, histamine is able to increase allergic inflammation by increasing Th2 cytokine production in a positive feedback dependent on H1R. This result could explain in part why H1R antagonists, are very efficient in rhinitis, but not in asthma.

CTLA-4-mediated regulatory phenotype of T-cells in tolerant lung recipients.

Obliterative bronchiolitis (OB) is the major cause of long-term lung allograft loss resulting from an unclear immune process occurring in the absence of the donor's immune cells. The present authors hypothesised that interactions of autologous dendritic cells (DCs) with T-cells could differ in OB patients compared with healthy lung transplant recipients (LTRs). Monocyte-derived DCs from 14 OB and 35 non-OB LTRs were cultured with autologous T-cells. T-regulatory (T(reg)) cells, co-receptors, cytokine production, DC phenotype and indoleamine 2,3-dioxygenase (IDO) expression were assessed by flow cytometry. Experiments were repeated in the presence of Pseudomonas aeruginosa or anti-co-receptor antibodies. DCs from non-OB LTR upregulated T(reg) cells, cytotoxic T-lymphocyte antigen (CTLA)-4 and interleukin (IL)-10. By contrast CD28 and inducible T-cell co-stimulator were downregulated concomitantly to IL-13 and IL-4. Compared to OB, non-OB DCs displayed an immature phenotype with lower CD80 and CD83 and higher IDO levels of expression. Stimulation by P. aeruginosa did not abolish the tolerogenic effects of DCs on non-OB T-cells. Finally, decreased T(reg) cells and IL-10 production were detected when adding anti-CTLA-4 antibodies in non-OB LTR. The present study demonstrates that dendritic cells from nonobliterative bronchiolitis lung transplant recipients induce a tolerant T-cell phenotype which is dependent on cytotoxic T-lymphocyte antigen-4 engagement.

[T regulatory lymphocytes, atopy and asthma: a new concept in three dimensions]. / Lymphocytes T régulateurs, atopie et asthme: un nouveau concept en trois dimensions.

BACKGROUND: Allergic inflammation is considered to be the result of a pattern of Th2 lymphocyte activation. However this inflammation, relevant for atopy and infiltration of affected tissues by eosinophils, is insufficient by itself to explain the clinical features of asthma. Several studies have demonstrated that Th2 type inflammation was also associated in asthma with a Th1 response, with production of gamma interferon. It has recently been shown that the regulatory T lymphocytes (Treg) which produce IL-10 and/or TGF-beta and induce tolerance are defective in allergic patients. In addition, these lymphocytes increase during specific immunotherapy. Their decrease could explain the Th2 activation found in atopic patients. PERSPECTIVE: We review the potential importance of Treg cells in atopy and also asthma, and propose a concept whereby the allergic inflammatory response would not be due to a Th1/Th2 imbalance, but rather to a Treg deficiency progressively rising from normal to atopic, from atopy to asthma and from asthma to acute exacerbations. CONCLUSION: Three dimensions of inflammation need therefore to be taken into account: Th1, Th2 and Treg.