Lentivirus IL-10 Gene Therapy Down-Regulates IL-17 and Attenuates Mouse Orthotopic Lung Allograft Rejection

Hirayama, S.; Sato, Masaaki; Loisel-Meyer, Séverine; Matsuda, Yasushi; Oishi, Hisashi; Guan, Z.; Saito, Tomohito; Yeung, Jonathan C.; Cypel, Marcelo; Hwang, David; Medin, Jeffrey A.; Liu, Mingyao; Keshavjee, Shaf

doi:10.1111/ajt.12230

Cited by 38 publications

(27 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…21,22,25,[34][35][36][37][38] We have found that fibrosis diminishes over time with surgical experience, and currently we observe minimal fibrosis in allografts not subjected to IRI, in contrast to our earlier data. Allograft fibrosis in the B10→B6 LT model is highly variable among different surgeons and research groups, whereas AR is mild but reproducible.…”

Section: Cold and Warm Ischemic Preservation Augment Allograft Fibrcontrasting

confidence: 92%

A B cell–dependent pathway drives chronic lung allograft rejection after ischemia–reperfusion injury in mice

Watanabe

Martinu

Chruscinski

et al. 2019

American Journal of Transplantation

View full text Add to dashboard Cite

Chronic lung allograft dysfunction (CLAD) limits long‐term survival after lung transplant (LT). Ischemia–reperfusion injury (IRI) promotes chronic rejection (CR) and CLAD, but the underlying mechanisms are not well understood. To examine mechanisms linking IRI to CR, a mouse orthotopic LT model using a minor alloantigen strain mismatch (C57BL/10 [B10, H‐2b] → C57BL/6 [B6, H‐2b]) and isograft controls (B6→B6) was used with antecedent minimal or prolonged graft storage. The latter resulted in IRI with subsequent airway and parenchymal fibrosis in prolonged storage allografts but not isografts. This pattern of CR after IRI was associated with the formation of B cell–rich tertiary lymphoid organs within the grafts and circulating autoantibodies. These processes were attenuated by B cell depletion, despite preservation of allograft T cell content. Our observations suggest that IRI may promote B cell recruitment that drives CR after LT. These observations have implications for the mechanisms leading to CLAD after LT.

show abstract

Section: Cold and Warm Ischemic Preservation Augment Allograft Fibrcontrasting

confidence: 92%

A B cell–dependent pathway drives chronic lung allograft rejection after ischemia–reperfusion injury in mice

Watanabe

Martinu

Chruscinski

et al. 2019

American Journal of Transplantation

View full text Add to dashboard Cite

show abstract

“…The previous study with this model found a similar incidence of OB, also using C57Bl/6N mice from Harlan Labs (7). However, a recent study did not find evidence of OB using C57Bl/10 lung transplanted to C57Bl/6J mice from Jackson labs (30). We also found the TCRδ −/− mice from Jackson and TCRδ +/− mice, mixed C57Bl/6N and C57Bl/6J background, had a decreased incidence of OB at 25%, although we still found similar pathology to the previous study (7).…”

Section: Discussionmentioning

confidence: 99%

CD4 T Cells but Not Th17 Cells Are Required for Mouse Lung Transplant Obliterative Bronchiolitis

Gupta

Suzuki

et al. 2015

American Journal of Transplantation

View full text Add to dashboard Cite

Lung transplant survival is limited by obliterative bronchiolitis (OB), but the mechanisms of OB development are unknown. Previous studies in a mouse model of orthotopic lung transplantation suggested a requirement for IL-17. We have used this orthotopic mouse model to investigate the source of IL-17A and the requirement for T cells producing IL-17A. The major sources of IL-17A were CD4+ T cells and γδ T cells. Depletion of CD4+ T cells led to a significantly decreased frequency and number of IL-17A+ lymphocytes and was sufficient to prevent acute rejection and OB. However, mice with STAT3-deficient T cells, which are unable to differentiate into Th17 cells, rejected lung allografts and developed OB similar to control mice. The frequency of IL-17A+ cells was not decreased in mice with STAT3-deficient T cells due mainly to the presence of IL-17A+ γδ T cells. Deficiency of γδ T cells also did not affect the development of airway fibrosis. Our data suggest that CD4+ T cells are required for OB development and expansion of IL-17A responses in the lung, while Th17 and γδ T cells are not absolutely required and may compensate for each other.

show abstract

“…They also might reasonably be the focus of possible new drugs or therapeutic approaches, such as the use of IL-10 or other anti-inflammatory biologic agents. Nevertheless, recent studies in patients with other forms of inflammatory liver diseases have not shown benefit of anti-TNF agents [44-47] or IL-10 [48-50], and the use of any of these agents would likely increase the risk of infections. Thus, they should be used in acute DILI only in the context of carefully designed clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Profiles of Serum Cytokines in Acute Drug-Induced Liver Injury and Their Prognostic Significance

et al. 2013

View full text Add to dashboard Cite

Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN) and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors) were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset). Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17) immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES) and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%), NPV = 97% (95% CI, 93%-100%), accuracy = 96% (95% CI, 92%-100%)]. ConclusionsAcute DILI is associated with robust and varying immune responses. High levels of expression of cytokines associated with innate immunity are associated with a poor prognosis, whereas high levels of expression of adaptive cytokines are associated with good long-term prognosis and eventual recovery. Serum immune analyte profiles at DILI onset appear to be of prognostic, and perhaps, diagnostic significance.

show abstract

Lentivirus IL-10 Gene Therapy Down-Regulates IL-17 and Attenuates Mouse Orthotopic Lung Allograft Rejection

Cited by 38 publications

References 40 publications

A B cell–dependent pathway drives chronic lung allograft rejection after ischemia–reperfusion injury in mice

A B cell–dependent pathway drives chronic lung allograft rejection after ischemia–reperfusion injury in mice

CD4 T Cells but Not Th17 Cells Are Required for Mouse Lung Transplant Obliterative Bronchiolitis

Profiles of Serum Cytokines in Acute Drug-Induced Liver Injury and Their Prognostic Significance

Contact Info

Product

Resources

About