Donor Batf3 inhibits murine lung allograft rejection and airway fibrosis

Watanabe, Tatsuaki; Lam, Christina; Oliver, Jillian; Oishi, Hisashi; Teskey, Grace; Beber, Samuel; Boonstra, K.; Umaña, Juan Mauricio; Buhari, H.; Joe, Betty; Guan, Z.; Horie, Miho; Keshavjee, S.; Martinu, T.; Juvet, S.

doi:10.1016/j.mucimm.2023.02.004

Cited by 4 publications

(3 citation statements)

References 57 publications

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“…However, to study donor IL-17RA deficiency, we had to switch the strains to B6-to-B10 transplants, since IL-17RA–deficient mice are commercially available only on the B6 background. B6-to-B10 transplantation shows less acute and chronic rejection pathology compared with B10-to-B6, as indicated in our prior studies ( 17 , 88 ). While the pathology was still sufficient to show a strong signal in our KO experiments, it is possible that the fibrotic processes differ between the 2 strain combinations.…”

Section: Discussionsupporting

confidence: 80%

Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection

Watanabe,

Juvet,

Berra

et al. 2023

JCI Insight

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Chronic lung allograft dysfunction (CLAD) is a major complication after lung transplantation that results from a complex interplay of innate inflammatory and alloimmune factors, culminating in parenchymal and/or obliterative airway fibrosis. Excessive IL-17A signaling and chronic inflammation have been recognized as key factors in these pathological processes. Herein, we developed a model of repeated airway inflammation in mouse minor alloantigen-mismatched single-lung transplantation. Repeated intratracheal LPS instillations augmented pulmonary IL-17A expression. LPS also increased acute rejection, airway epithelial damage, and obliterative airway fibrosis, similar to human explanted lung allografts with antecedent episodes of airway infection. We then investigated the role of donor and recipient IL-17 receptor A (IL-17RA) in this context. Donor IL-17RA deficiency significantly attenuated acute rejection and CLAD features, whereas recipient IL-17RA deficiency only slightly reduced airway obliteration in LPS allografts. IL-17RA immunofluorescence positive staining was greater in human CLAD lungs compared with control human lung specimens, with localization to fibroblasts and myofibroblasts, which was also seen in mouse LPS allografts. Taken together, repeated airway inflammation after lung transplantation caused local airway epithelial damage, with persistent elevation of IL-17A and IL-17RA expression and particular involvement of IL-17RA on donor structural cells in development of fibrosis.

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Section: Discussionsupporting

confidence: 80%

Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection

Watanabe,

Juvet,

Berra

et al. 2023

JCI Insight

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“…Their sustained elevation at day 35 in allografts underscores their integral role in the development of rejection, aligning with findings by Vandermeulen et al that identified increased dendritic cells in CLADrelated phenotypes [25]. By presenting allo-antigens to the recipient's immune system, a chronic immune response develops; therefore, dendritic cells probably play a crucial role in pulmonary rejection and CLAD [26].…”

Section: Discussionsupporting

confidence: 79%

The Immunopathology of Pulmonary Rejection after Murine Lung Transplantation

Kaes,

Pollenus,

Hooft

et al. 2024

Cells

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To improve outcomes following lung transplantation, it is essential to understand the immunological mechanisms that result in chronic graft failure. The associated clinical syndrome is termed chronic lung allograft dysfunction (CLAD), which is known to be induced by alloimmune-dependent (i.e., rejection) and alloimmune-independent factors (e.g., infections, reflux and environmental factors). We aimed to explore the alloimmune-related mechanism, i.e., pulmonary rejection. In this study, we use a murine orthotopic left lung transplant model using isografts and allografts (C57BL/6 or BALB/c as donors to C57BL/6 recipients), with daily immunosuppression (10 mg/kg cyclosporin A and 1.6 mg/kg methylprednisolone). Serial sacrifice was performed at days 1, 7 and 35 post-transplantation (n = 6 at each time point for each group). Left transplanted lungs were harvested, a single-cell suspension was made and absolute numbers of immune cells were quantified using multicolor flow cytometry. The rejection process followed the principles of a classic immune response, including innate but mainly adaptive immune cells. At day 7 following transplantation, the numbers of interstitial macrophages, monocytes, dendritic cells, NK cells, NKT cells, CD4+ T cells and CD8+ T and B cells were increased in allografts compared with isografts. Only dendritic cells and CD4+ T cells remained elevated at day 35 in allografts. Our study provides insights into the immunological mechanisms of true pulmonary rejection after murine lung transplantation. These results might be important in further research on diagnostic evaluation and treatment for CLAD.

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“…However, some other studies suggested that DCs might ameliorate tissue fibrosis [64]. The conditional DC depletion after discontinuation of the liver insult in a mouse model led to delayed fibrosis regression, while the adoptive transfer of purified DCs accelerated liver fibrosis regression, which was partially dependent on MMP‐9 produced by DCs [65].…”

Section: The Inflamed Immune Microenvironment Of Rifmentioning

confidence: 99%

Radiation‐induced fibrosis: Mechanisms and therapeutic strategies from an immune microenvironment perspective

Zheng,

Liu,

2024

Immunology

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Radiation‐induced fibrosis (RIF) is a severe chronic complication of radiotherapy (RT) manifested by excessive extracellular matrix (ECM) components deposition within the irradiated area. The lung, heart, skin, jaw, pelvic organs and so on may be affected by RIF, which hampers body functions and quality of life. There is accumulating evidence suggesting that the immune microenvironment may play a key regulatory role in RIF. This article discussed the synergetic or antagonistic effects of immune cells and mediators in regulating RIF's development. Several potential preventative and therapeutic strategies for RIF were proposed based on the immunological mechanisms to provide clinicians with improved cognition and clinical treatment guidance.

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Donor Batf3 inhibits murine lung allograft rejection and airway fibrosis

Cited by 4 publications

References 57 publications

Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection

Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection

The Immunopathology of Pulmonary Rejection after Murine Lung Transplantation

Radiation‐induced fibrosis: Mechanisms and therapeutic strategies from an immune microenvironment perspective

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