Defining a natural killer cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies

Gauthier, P.; Macková, Martina; Hirji, A.; Weinkauf, J.; Timofte, I.; Snell, Greg; Westall, Glen P.; Havlín, Jan; Lischke, Robert; Zajacova, Andrea; Šimonek, Jan; Hachem, Ramsey R.; Kreisel, Daniel; Levine, Deborah J.; Kubisa, Bartosz; Piotrowska, Maria; Juvet, S.; Keshavjee, Shaf; Jaksch, Péter; Klepetko, Walter; Halloran, K.; Halloran, Philip F.

doi:10.1016/j.ajt.2023.06.003

Cited by 5 publications

(2 citation statements)

References 46 publications

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“…Gene expression microarray analysis of 896 transbronchial biopsies revealed a natural killer (NK) cell-enriched molecular rejection-like state, a T cell-mediated rejection/mixed state and no rejection. Only a T-cell mediated rejection/mixed state was associated with CLAD, while NK cell-enriched molecular state was not [19]. Along these lines, a gene expression microarray comparison between mucosal biopsies at the third generation of airway branching and transbronchial biopsies was performed, which revealed that there is a diffuse molecular injury signature that impacts prognosis indicating that both have their value in assessing CLAD risk in LTx [20].…”

Section: Andandmentioning

confidence: 99%

The diagnosis and management of chronic lung allograft dysfunction

Verleden,

Hendriks,

Verleden

2024

Current Opinion in Pulmonary Medicine

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Purpose of review Chronic lung allograft dysfunction (CLAD) remains a life-threatening complication following lung transplantation. Different CLAD phenotypes have recently been defined, based on the combination of pulmonary function testing and chest computed tomography (CT) scanning and spurred renewed interests in differential diagnosis, risk factors and management of CLAD. Recent findings Given their crucial importance in the differential diagnosis, we will discuss the latest development in assessing the pulmonary function and chest CT scan, but also their limitations in proper CLAD phenotyping, especially with regards to patients with baseline allograft dysfunction. Since no definitive treatment exists, it remains important to timely identify clinical risk factors, but also to assess the presence of specific patterns or biomarkers in tissue or in broncho alveolar lavage in relation to CLAD (phenotypes). We will provide a comprehensive overview of the latest advances in risk factors and biomarker research in CLAD. Lastly, we will also review novel preventive and curative treatment strategies for CLAD. Summary Although this knowledge has significantly advanced the field of lung transplantation, more research is warranted because CLAD remains a life-threatening complication for all lung transplant recipients.

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Section: Andandmentioning

confidence: 99%

The diagnosis and management of chronic lung allograft dysfunction

Verleden,

Hendriks,

Verleden

2024

Current Opinion in Pulmonary Medicine

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“…Gene expression analysis in graft biopsies fostered the characterization of ABMR, especially after KT, and showed comparable molecular signatures of ABMR in kidney, heart and lung transplants [11][12][13][14][15] , with comparable risk of graft loss in kidney transplant recipients based on their molecular profile irrespective of clinical differences 16 . Similar gene expression analyses have already identified intrahepatic molecular signatures of spontaneous operational tolerance, of TCMR but, most importantly, not of ABMR [17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

Molecular signatures of chronic antibody-mediated rejection in human liver transplants

Engel,

Alaswad,

Campos-Murguia

et al. 2024

Preprint

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Background&Aims: The role of antibody-mediated rejection (ABMR) after liver transplantation (LT) remains controversial. Chronic ABMR (cABMR) is often subclinical and potentially missed without surveillance biopsies (svLbx) which are not established in most LT centers. Transcriptome analysis previously characterized molecular changes in T cell-mediated rejection (TCMR) after solid organ transplantation. We aimed to identify molecular cABMR signatures after LT for a more comprehensive understanding of cABMR. Methods: We retrospectively identified indication and svLbx from our prospective institutional biorepository (n=1207 over 12 years). We performed RNA-sequencing on liver biopsies (discovery cohort: n=71; validation cohort: n=58). Downstream analyses explored the unique and common molecular features of cABMR, clinical (clinTCMR) and subclinical TCMR (subTCMR) compared to no histological rejection (NHR). Results: Nineteen percent of LT recipients with donor-specific antibodies had cABMR. Eighty-one percent of patients with cABMR had ALT and AST ≤2x the upper limit of normal, only being recognized by svLbx. The cABMR group displayed differentially expressed genes (DEGs) uniquely enriched in fibrogenesis-, complement activation- and TNFα-signaling-related pathways. ClinTCMR showed DEGs uniquely enriched in antigen presentation-, interferon-signaling-, and T cell receptor-signaling-related pathways. Common cABMR and clinTCMR DEGs were enriched in chemokine-signaling- and cytokine response-related pathways. Gene set enrichment scores of interferon-signaling and extracellular matrix remodeling pathways discriminated cABMR and clinTCMR. Molecular signatures of clinTCMR correlated with histological TCMR-patterns. Molecular cABMR-signatures correlated with lobular graft injury and liver fibrosis scores. The validation cohort consistently showed patterns of DEGs associating cABMR with fibrogenesis- and NF-κB-signaling-related pathways and clinTCMR with interferon-signaling- and adaptive immunity-related pathways. SubTCMR was molecularly almost indistinguishable from NHR. Conclusions: We report transcriptome-unique features of cABMR that is a unique molecular identity associated with inflammation and fibrogenesis.

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Theseus and the search for an antibody-mediated rejection molecular state in lung transplant biopsies

Calabrese¹,

Greenland²

2023

American Journal of Transplantation

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Defining a natural killer cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies

Cited by 5 publications

References 46 publications

The diagnosis and management of chronic lung allograft dysfunction

The diagnosis and management of chronic lung allograft dysfunction

Molecular signatures of chronic antibody-mediated rejection in human liver transplants

Theseus and the search for an antibody-mediated rejection molecular state in lung transplant biopsies

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