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  1. Article ; Online: Single center study investigating the clinical association of donor-derived cell-free DNA with acute outcomes in lung transplantation

    Kentaro Noda / Mark E. Snyder / Qingyong Xu / David Peters / John F. McDyer / Adriana Zeevi / Pablo G. Sanchez

    Frontiers in Transplantation, Vol

    2024  Volume 2

    Abstract: BackgroundCirculating donor-derived cell-free DNA (dd-cfDNA) levels have been proposed as a potential tool for the diagnosis of graft injury. In this study, we prospectively investigated dd-cfDNA plasma levels and their association with severe primary ... ...

    Abstract BackgroundCirculating donor-derived cell-free DNA (dd-cfDNA) levels have been proposed as a potential tool for the diagnosis of graft injury. In this study, we prospectively investigated dd-cfDNA plasma levels and their association with severe primary graft dysfunction (PGD) and graft rejection after lung transplant.MethodsA total of 40 subjects undergoing de-novo lung transplants at our institution were recruited in this study. Blood samples were collected at various time points before and after lung transplant for 1 year. Dd-cfDNA in samples was determined using AlloSure assay (CareDx Inc.). The correlation of the value of %dd-cfDNA was investigated with the incidence of PGD, acute cellular rejection (ACR), and donor-specific antibody.ResultsWe observed a rapid increase of %dd-cfDNA in the blood of recipients after lung transplantation compared to baseline. The levels of dd-cfDNA decreased during the first two weeks. The peak was observed within 72 h after transplantation. The peak values of %dd-cfDNA varied among subjects and did not correlate with severe PGD incidence. We observed an association between levels of %dd-cfDNA from blood collected at the time of transbronchial biopsy and the histological diagnosis of ACR at 3 weeks.ConclusionOur data show that circulating dd-cfDNA levels are associated with ACR early after transplantation but not with severe PGD. Plasma levels of dd-cfDNA may be a less invasive tool to estimate graft rejection after lung transplantation however larger studies are still necessary to better identify thresholds.
    Keywords lung transplantation ; donor-derived cell-free DNA ; primary grafts dysfunction ; acute cellular rejection ; antibody-mediated rejection ; Specialties of internal medicine ; RC581-951
    Subject code 610
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Heparanase inhibition preserves the endothelial glycocalyx in lung grafts and improves lung preservation and transplant outcomes

    Kentaro Noda / Brian J. Philips / Mark E. Snyder / Julie A. Phillippi / Mara Sullivan / Donna B. Stolz / Xi Ren / James D. Luketich / Pablo G. Sanchez

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 12

    Abstract: Abstract The endothelial glycocalyx (eGC) is considered a key regulator of several mechanisms that prevent vascular injury and disease. Degradation of this macromolecular layer may be associated with post-transplant graft dysfunction. In this study, we ... ...

    Abstract Abstract The endothelial glycocalyx (eGC) is considered a key regulator of several mechanisms that prevent vascular injury and disease. Degradation of this macromolecular layer may be associated with post-transplant graft dysfunction. In this study, we aimed to demonstrate the benefits of eGC protection via heparanase inhibition on graft quality. We established rat models of lung grafts with damaged or preserved eGC using ischemic insult and transplanted the grafts into recipients. Lung grafts were also subjected to normothermic ex vivo lung perfusion for detailed assessment under isolated conditions. Physiologic parameters and eGC-associated cellular events were assessed in grafts before and after reperfusion. Structurally degraded eGC and highly activated heparanase were confirmed in lungs with ischemic insult. After transplant, lungs with damaged eGC exhibited impaired graft function, inflammation, edema, and inflammatory cell migration. Increased eGC shedding was evident in the lungs after reperfusion both in vivo and ex vivo. These reperfusion-related deficiencies were significantly attenuated in lungs with preserved eGC following heparanase inhibition. Our studies demonstrated that eGC plays a key role in maintaining lung graft quality and function. Heparanase inhibition may serve as a potential therapeutic to preserve eGC integrity, leading to improved post-transplant outcomes.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Immune and epithelial determinants of age-related risk and alveolar injury in fatal COVID-19

    Michael Chait / Mine M. Yilmaz / Shanila Shakil / Amy W. Ku / Pranay Dogra / Thomas J. Connors / Peter A. Szabo / Joshua I. Gray / Steven B. Wells / Masaru Kubota / Rei Matsumoto / Maya M.L. Poon / Mark E. Snyder / Matthew R. Baldwin / Peter A. Sims / Anjali Saqi / Donna L. Farber / Stuart P. Weisberg

    JCI Insight, Vol 7, Iss

    2022  Volume 11

    Abstract: Respiratory failure in COVID-19 is characterized by widespread disruption of the lung’s alveolar gas exchange interface. To elucidate determinants of alveolar lung damage, we performed epithelial and immune cell profiling in lungs from 24 COVID-19 ... ...

    Abstract Respiratory failure in COVID-19 is characterized by widespread disruption of the lung’s alveolar gas exchange interface. To elucidate determinants of alveolar lung damage, we performed epithelial and immune cell profiling in lungs from 24 COVID-19 autopsies and 43 uninfected organ donors ages 18–92 years. We found marked loss of type 2 alveolar epithelial (T2AE) cells and increased perialveolar lymphocyte cytotoxicity in all fatal COVID-19 cases, even at early stages before typical patterns of acute lung injury are histologically apparent. In lungs from uninfected organ donors, there was also progressive loss of T2AE cells with increasing age, which may increase susceptibility to COVID-19–mediated lung damage in older individuals. In the fatal COVID-19 cases, macrophage infiltration differed according to the histopathological pattern of lung injury. In cases with acute lung injury, we found accumulation of CD4+ macrophages that expressed distinctly high levels of T cell activation and costimulation genes and strongly correlated with increased extent of alveolar epithelial cell depletion and CD8+ T cell cytotoxicity. Together, our results show that T2AE cell deficiency may underlie age-related COVID-19 risk and initiate alveolar dysfunction shortly after infection, and we define immune cell mediators that may contribute to alveolar injury in distinct pathological stages of fatal COVID-19.
    Keywords Aging ; COVID-19 ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease

    Peter A. Szabo / Hanna Mendes Levitin / Michelle Miron / Mark E. Snyder / Takashi Senda / Jinzhou Yuan / Yim Ling Cheng / Erin C. Bush / Pranay Dogra / Puspa Thapa / Donna L. Farber / Peter A. Sims

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 16

    Abstract: Immune cells are shaped by the tissue environment, yet the states of healthy human T cells are mainly studied in the blood. Here, the authors perform single cell RNA-seq of T cells from tissues and blood of healthy donors and show its utility as a ... ...

    Abstract Immune cells are shaped by the tissue environment, yet the states of healthy human T cells are mainly studied in the blood. Here, the authors perform single cell RNA-seq of T cells from tissues and blood of healthy donors and show its utility as a reference map for comparison of human T cell states in disease.
    Keywords Science ; Q
    Language English
    Publishing date 2019-10-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease

    Peter A. Szabo / Hanna Mendes Levitin / Michelle Miron / Mark E. Snyder / Takashi Senda / Jinzhou Yuan / Yim Ling Cheng / Erin C. Bush / Pranay Dogra / Puspa Thapa / Donna L. Farber / Peter A. Sims

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 16

    Abstract: Immune cells are shaped by the tissue environment, yet the states of healthy human T cells are mainly studied in the blood. Here, the authors perform single cell RNA-seq of T cells from tissues and blood of healthy donors and show its utility as a ... ...

    Abstract Immune cells are shaped by the tissue environment, yet the states of healthy human T cells are mainly studied in the blood. Here, the authors perform single cell RNA-seq of T cells from tissues and blood of healthy donors and show its utility as a reference map for comparison of human T cell states in disease.
    Keywords Science ; Q
    Language English
    Publishing date 2019-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Tissue-Resident Memory T Cells Mediate Immune Homeostasis in the Human Pancreas through the PD-1/PD-L1 Pathway

    Stuart P. Weisberg / Dustin J. Carpenter / Michael Chait / Pranay Dogra / Robyn D. Gartrell-Corrado / Andrew X. Chen / Sean Campbell / Wei Liu / Pooja Saraf / Mark E. Snyder / Masaru Kubota / Nichole M. Danzl / Beth A. Schrope / Raul Rabadan / Yvonne Saenger / Xiaojuan Chen / Donna L. Farber

    Cell Reports, Vol 29, Iss 12, Pp 3916-3932.e

    2019  Volume 5

    Abstract: Summary: Non-recirculating tissue-resident memory T cells (TRMs) are the predominant T cell subset in diverse tissue sites, where they mediate protective immune responses in situ. Here, we reveal a role for TRM in maintaining immune homeostasis in the ... ...

    Abstract Summary: Non-recirculating tissue-resident memory T cells (TRMs) are the predominant T cell subset in diverse tissue sites, where they mediate protective immune responses in situ. Here, we reveal a role for TRM in maintaining immune homeostasis in the human pancreas through interactions with resident macrophages and the PD-1/PD-L1 inhibitory pathway. Using tissues obtained from organ donors, we identify that pancreas T cells comprise CD8+PD-1hi TRMs, which are phenotypically, functionally, and transcriptionally distinct compared to TRMs in neighboring jejunum and lymph node sites. Pancreas TRMs cluster with resident macrophages throughout the exocrine areas; TRM effector functions are enhanced by macrophage-derived co-stimulation and attenuated by the PD-1/PD-L1 pathways. Conversely, in samples from chronic pancreatitis, TRMs exhibit reduced PD-1 expression and reduced interactions with macrophages. These findings suggest important roles for PD-1 and TRM-macrophage interactions in controlling tissue homeostasis and immune dysfunctions underlying inflammatory disease, with important implications for PD-1-based immunotherapies. : Non-recirculating tissue-resident memory T cells (TRMs) mediate immune responses in non-lymphoid tissues. Using a human organ donor tissue resource, Weisberg et al. reveal that PD-1hi pancreas TRMs are regulated by PD-L1+ macrophages during homeostasis. Comparison with chronic pancreatitis patient samples shows how pancreas TRM regulation is altered during inflammation. Keywords: memory T cells, pancreas, chronic pancreatitis, tissue immunity, mucosal immunity, PD-1, macrophage
    Keywords Biology (General) ; QH301-705.5
    Subject code 616 ; 610
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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