Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 13, Issue 3, Pages 611-620Publisher
WILEY-BLACKWELL
DOI: 10.1111/ajt.12067
Keywords
Bronchiolitis obliterans; cyclosporine A; obliterative airway disease; T cells; transplantation and immunology
Categories
Funding
- Walloon Region
- FNRS-Belgium
- GlaxoSmithKline Biologicals
- FNRS (Fonds National de la Recherche Scientifique, Belgium)
- Fonds Erasme (Universite Libre de Bruxelles, Brussels, Belgium)
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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- 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.
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