title: Cyclosporine A drives a Th17- and Th2-mediated posttransplant obliterative airway disease.
abstract: Calcineurin-inhibitor refractory bronchiolitis obliterans (BO) represents the leading cause of late graft failure after lung transplantation. T helper (Th)2 and Th17 lymphocytes have been associated with BO development. Taking advantage of a fully allogeneic trachea transplantation model in mice, we addressed the pathogenicity of Th cells in obliterative airway disease (OAD) occurring in cyclosporine A (CsA)-treated recipients. We found that CsA prevented CD8(+)  T cell infiltration into the graft and downregulated the Th1 response but affected neither Th2 nor Th17 responses in vivo. In secondary mixed lymphocyte cultures, CsA dramatically decreased donor-specific IFN-γ production, enhanced IL-17 production and did not affect IL-13. As CD4(+)  depletion efficiently prevented OAD in CsA-treated recipients, we further explored the role of Th2 and Th17 immunity in vivo. Although IL-4 and IL-17 deficient untreated mice developed an OAD comparable to wild-type recipients, a single cytokine deficiency afforded significant protection in CsA-treated recipients. In conclusion, CsA treatment unbalances T helper alloreactivity and favors Th2 and Th17 as coexisting pathways mediating chronic rejection of heterotopic tracheal allografts.
authors: Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium. plemaitr@ulb.ac.be
authors: P H
authors: PH
authors: Lemaître
authors: B
authors: B
authors: Vokaer
authors: L-M
authors: LM
authors: Charbonnier
authors: Y
authors: Y
authors: Iwakura
authors: K A
authors: KA
authors: Field
authors: M
authors: M
authors: Estenne
authors: M
authors: M
authors: Goldman
authors: O
authors: O
authors: Leo
authors: M
authors: M
authors: Remmelink
authors: A
authors: A
authors: Le Moine
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001989:Bronchiolitis Obliterans / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D016572:Cyclosporine / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006084:Graft Rejection / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000633:toxicity; D007371:Interferon-gamma / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology; D016040:Lung Transplantation / Q000009:adverse effects*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000276:immunology*; D014132:Trachea / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine