Chronic lung allograft dysfunction (CLAD) is the major cause of failure, accounting for >40% of deaths beyond the first year post-LTx. Lung transplant recipients (LTRs) have 1-, 5-, and 10-year unadjusted survival rates of 80%, 54%, and 32%, respectively ( 2). Lung transplantation (LTx) has still a poor long-term outcome, with a current median post-transplant survival of 6.5 years ( 1). Such a signature may be of interest for the monitoring of LTRs and may allow an early stratification of LTRs at risk of CLAD. Our findings propose that the presence of dysfunctional HCMV-specific HLA-E-restricted CD8 T cells together with post-infection changes in the immune cell distribution affecting NK and γδT cells defines an early immune signature for CLAD in HCMV + LTRs. In CLAD LTRs, the regulation of B, total CD8 T, and δ2 +γδT cells is maintained, but total NK, CD57 +/NKG2C + NK, and δ2 −γδT subsets are markedly reduced, while CD57 is overexpressed across T lymphocytes.Ĭonclusions: CLAD is associated with significant changes in anti-HCMV immune cell responses. In STABLE LTRs, HCMV primary infection causes a decrease in B cells and inflation of CD8 T, CD57 +/NKG2C + NK, and δ2 −γδT cells. Immunophenotype reveals an altered expression profile for HLA-EUL40 CD8 T in CLAD patients with a decreased expression for CD56 and the acquisition of PD-1. The frequency of HLA-EUL40 and HLA-A2pp65 CD8 T among blood CD8 T cells shows lower median values in CLAD LTRs. In contrast, HLA-A2pp65 CD8 T was equally detected in 45% of STABLE and 47.8% of CLAD LTRs. Results: At M18 post-transplantation, HLA-EUL40 CD8 T responses were less frequently found in HCMV + LTRs (21.7%) developing CLAD (CLAD) than in LTRs (55%) keeping a functional graft (STABLE). The homeostasis of immune subsets (B, CD4T, CD8 T, NK, and γδT cells) post-primary infection associated with CLAD was also investigated. Methods: This study quantified and phenotyped conventional (HLA-A2pp65) and HLA-E-restricted (HLA-EUL40) anti-HCMV CD8 + T (CD8 T) cell responses induced by infection in LTRs developing CLAD or maintaining a stable allograft. This study investigated the HCMV immunity in LTRs who will develop CLAD. Currently, no treatment is available to reverse CLAD after diagnosis, and the identification of reliable biomarkers that can predict the early development of CLAD is needed. The complex interplay between HCMV and allograft rejection is still unclear. 18CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, Franceīackground: Human cytomegalovirus (HCMV) infection is common and often severe in lung transplant recipients (LTRs), and it is a risk factor associated with chronic lung allograft dysfunction (CLAD).17CHU Nantes, Nantes Université, Laboratoire de Virologie, Nantes, France.16Service de Pneumologie, Hôpital Européen Georges-Pompidou, Paris, France.15CHU de Toulouse, Hôpital Larrey, Toulouse, France.14Service Hospitalier Universitaire Pneumologie et Physiologie, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, Grenoble, France.13Physiopathology and Epidemiology of Respiratory Diseases, UMR1152 INSERM and Université de Paris, Paris, France.12APHP, Nord-Université Paris Cité, Hôpital Bichat-Claude Bernard, Service de Pneumologie B et Transplantation Pulmonaire, Paris, France.11Hospices Civils de Lyon, GHE, Service de Pneumologie, Inserm, Lyon, France.10Université de Lyon, Université Lyon1, INRAE, IVPC, Lyon, France.
4Hôpital Foch, Service de pneumologie, Suresnes, France.3CHU de Marseille, APHM, Hôpital Nord, Service de Pneumologie et Equipe de Transplantation pulmonaire Marseille, France Aix-Marseille Université, Marseille, France.2Nantes Université, CHU Nantes, Service de Pneumologie, Institut du thorax, Nantes, France.1Nantes Université, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, Nantes, France.Amélie Rousselière 1, Laurence Delbos 1, Aurore Foureau 1,2, Martine Reynaud-Gaubert 3, Antoine Roux 4, Xavier Demant 5, Jérôme Le Pavec 6,7,8, Romain Kessler 9, Jean-François Mornex 10,11, Jonathan Messika 12,13, Loïc Falque 14, Aurélie Le Borgne 15, Véronique Boussaud 16, Adrien Tissot 1,2, Sophie Hombourger 1, Céline Bressollette-Bodin 1,17 and Béatrice Charreau 1,18*
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