title: Impaired CD8(+) T cell immunity after allogeneic bone marrow transplantation leads to persistent and severe respiratory viral infection.
abstract: BACKGROUND
  Bone marrow transplant (BMT) recipients experience frequent and severe respiratory viral infections (RVIs). However, the immunological mechanisms predisposing to RVIs are uncertain. Therefore, we hypothesized that antiviral T cell immunity is impaired as a consequence of allogeneic BMT, independent of pharmacologic immunosuppression, and is responsible for increased susceptibility to RVI.
  
  
  METHODS
  Bone marrow and splenocytes from C57BL/6(H2(b)) mice were transplanted into B10.BR(H2(k)) (Allo) or C57BL/6(H2(b)) (Syn) recipients. Five weeks after transplantation, recipient mice were inoculated intranasally with mouse parainfluenza virus type 1 (mPIV-1), commonly known as Sendai virus (SeV), and monitored for relevant immunological and disease endpoints.
  
  
  RESULTS
  Severe and persistent airway inflammation, epithelial injury, and enhanced mortality are found after viral infection in Allo mice but not in control Syn and non-transplanted mice. In addition, viral clearance is delayed in Allo mice as evidenced by prolonged detection of viral transcripts at Day 15 post-inoculation (p.i.) but not in control mice. In concert with these events, we also detected decreased levels of total and virus-specific CD8(+) T cells, as well as increased T cellexpression of inhibitory receptor programmed death-1 (PD-1), in the lungs of Allo mice at Day 8 p.i. Adoptive transfer of CD8(+) T cells from non-transplanted mice recovered from SeV infection into Allo mice at Day 8 p.i. restored normal levels of viral clearance, epithelial repair, and lung inflammation.
  
  
  CONCLUSIONS
  Taken together these results indicate that allogeneic BMT results in more severe RVI based on the failure to develop an appropriate pulmonary CD8(+) T cell response, providing an important potential mechanism to target in improving outcomes of RVI after BMT.
authors.affiliation: Duke University Medical Center, Durham, NC, 27710, United States. Electronic address: kymberly.gowdy@nih.gov.
authors.forename: Kymberly M
authors.initials: KM
authors.lastname: Gowdy
authors.affiliation: Duke University Medical Center, Durham, NC, 27710, United States.
authors.forename: Tereza
authors.initials: T
authors.lastname: Martinu
authors.affiliation: Duke University Medical Center, Durham, NC, 27710, United States.
authors.forename: Julia L
authors.initials: JL
authors.lastname: Nugent
authors.affiliation: Duke University Medical Center, Durham, NC, 27710, United States.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Manzo
authors.affiliation: Duke University Medical Center, Durham, NC, 27710, United States.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Zhang
authors.affiliation: Duke University Medical Center, Durham, NC, 27710, United States.
authors.forename: Francine L
authors.initials: FL
authors.lastname: Kelly
authors.affiliation: Washington University School of Medicine, St. Louis, MO, 63110, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.affiliation: Duke University Medical Center, Durham, NC, 27710, United States; Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Palmer
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D007111:Immunity, Cellular; D008297:Male; D051379:Mice; D012141:Respiratory Tract Infections / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D010253:Respirovirus Infections / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D029082:Sendai virus / Q000276:immunology*
keywords: Bone marrow transplant; CD8(+) T cells; Lung; Respiratory virus