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  1. Article ; Online: Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor–induced diabetes

    Ana Luisa Perdigoto / Songyan Deng / Katherine C. Du / Manik Kuchroo / Daniel B. Burkhardt / Alexander Tong / Gary Israel / Marie E. Robert / Stuart P. Weisberg / Nancy Kirkiles-Smith / Angeliki M. Stamatouli / Harriet M. Kluger / Zoe Quandt / Arabella Young / Mei-Ling Yang / Mark J. Mamula / Jordan S. Pober / Mark S. Anderson / Smita Krishnaswamy /
    Kevan C. Herold

    JCI Insight, Vol 7, Iss

    2022  Volume 17

    Abstract: Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes ...

    Abstract Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti–PD-L1 but not anti–CTLA-4 induced diabetes rapidly. RNA sequencing revealed that cytolytic IFN-γ+CD8+ T cells infiltrated islets with anti–PD-L1. Changes in β cells were predominantly driven by IFN-γ and TNF-α and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFN-γ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti–IFN-γ and anti–TNF-α prevented CPI-DM in anti–PD-L1–treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway resulted in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
    Keywords Autoimmunity ; Medicine ; R
    Subject code 570
    Language English
    Publishing date 2022-09-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. 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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  3. Article ; Online: A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

    Calvin C. Chan / Isaac T. W. Harley / Paul T. Pfluger / Aurelien Trompette / Traci E. Stankiewicz / Jessica L. Allen / Maria E. Moreno-Fernandez / Michelle S. M. A. Damen / Jarren R. Oates / Pablo C. Alarcon / Jessica R. Doll / Matthew J. Flick / Leah M. Flick / Joan Sanchez-Gurmaches / Rajib Mukherjee / Rebekah Karns / Michael Helmrath / Thomas H. Inge / Stuart P. Weisberg /
    Sünje J. Pamp / David A. Relman / Randy J. Seeley / Matthias H. Tschöp / Christopher L. Karp / Senad Divanovic

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 16

    Abstract: Interactions between the immune system and adipose tissue contribute to the regulation of body weight, however, the underlying mechanisms remain incompletely understood. Here the authors dissect the role of two structurally and functionally similar ... ...

    Abstract Interactions between the immune system and adipose tissue contribute to the regulation of body weight, however, the underlying mechanisms remain incompletely understood. Here the authors dissect the role of two structurally and functionally similar immune mediators, BAFF and APRIL, in modifying diet-induced weight gain and adipocyte lipid handling.
    Keywords Science ; Q
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. 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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  5. Article ; Online: ZFX Controls Propagation and Prevents Differentiation of Acute T-Lymphoblastic and Myeloid Leukemia

    Stuart P. Weisberg / Matthew R. Smith-Raska / Jose M. Esquilin / Ji Zhang / Teresita L. Arenzana / Colleen M. Lau / Michael Churchill / Haiyan Pan / Apostolos Klinakis / Jack E. Dixon / Leonid A. Mirny / Siddhartha Mukherjee / Boris Reizis

    Cell Reports, Vol 6, Iss 3, Pp 528-

    2014  Volume 540

    Abstract: Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic ... ...

    Abstract Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator.
    Keywords Biology (General) ; QH301-705.5
    Subject code 572 ; 610
    Language English
    Publishing date 2014-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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