title: Long-Term Persistence of Donor Alveolar Macrophages in Human Lung Transplant Recipients That Influences Donor-Specific Immune Responses.
abstract: Steady-state alveolar macrophages (AMs) are long-lived lung-resident macrophages with sentinel function. Evidence suggests that AM precursors originate during embryogenesis and populate lungs without replenishment by circulating leukocytes. However, their presence and persistence are unclear following human lung transplantation (LTx). Our goal was to examine donor AM longevity and evaluate whether AMs of recipient origin seed the transplanted lungs. Origin of AMs was accessed using donor-recipient HLA mismatches. We demonstrate that 94-100% of AMs present in bronchoalveolar lavage (BAL) were donor derived and, importantly, AMs of recipient origin were not detected. Further, analysis of BAL cells up to 3.5 years post-LTx revealed that the majority of AMs (>87%) was donor derived. Elicitation of de novo donor-specific antibody (DSA) is a major post-LTx complication and a risk factor for development of chronic rejection. The donor AMs responded to anti-HLA framework antibody (Ab) with secretion of inflammatory cytokines. Further, in an experimental murine model, we demonstrate that adoptive transfer of allogeneic AMs stimulated humoral and cellular immune responses to alloantigen and lung-associated self-antigens and led to bronchiolar obstruction. Therefore, donor-derived AMs play an essential role in the DSA-induced inflammatory cascade leading to obliterative airway disease of the transplanted lungs.
authors.affiliation: Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.|Department of Surgery, Washington University School of Medicine, Saint Louis, MO.
authors.forename: D K
authors.initials: DK
authors.lastname: Nayak
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, MO.
authors.forename: F
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, MO.
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.affiliation: HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, Affiliate of Rockefeller University, New York, NY.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.affiliation: HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, Affiliate of Rockefeller University, New York, NY.
authors.forename: M
authors.initials: M
authors.lastname: Tsuji
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, MO.
authors.forename: R
authors.initials: R
authors.lastname: Hachem
authors.affiliation: Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.|Department of Surgery, Washington University School of Medicine, Saint Louis, MO.|Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO.
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000402:Airway Obstruction / Q000276:immunology; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection / Q000453:epidemiology / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007518:Isoantibodies / Q000276:immunology*; D008171:Lung Diseases / Q000276:immunology* / Q000601:surgery; D016040:Lung Transplantation; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000276:immunology; D014019:Tissue Donors / Q000600:supply & distribution*; D066027:Transplant Recipients
chemical_list: D001324:Autoantigens; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D007518:Isoantibodies
keywords: alloantibody; animal model; basic (laboratory) research/science; bronchiolitis obliterans (BOS); clinical research/practice; immunosuppression/immune modulation; lung (allograft) function/dysfunction; lung transplantation/pulmonology; macrophage/monocyte biology