Browsing by Subject "T-lymphocytes"

Now showing 1 - 4 of 4
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    CAR T-cell toxicities: from bedside to bench, how novel toxicities inform laboratory investigations
    (American Society of Hematology, 2024) Perna, Fabiana; Parekh, Samir; Diorio, Caroline; Smith, Melody; Subklewe, Marion; Mehta, Rakesh; Locke, Frederick L.; Shah, Nirali N.; Medicine, School of Medicine
    Multiple chimeric antigen receptor (CAR) T-cell therapies are US Food and Drug Administration-approved, and several are under development. Although effective for some cancers, toxicities remain a limitation. The most common toxicities, that is, cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, are well described. With increasing utilization, providers worldwide are reporting other emergent and often complicated toxicities. Given the evolving toxicity profiles and urgent need to catalog these emerging and emergent CAR T-cell toxicities and describe management approaches, the American Society of Hematology Subcommittee on Emerging Gene and Cell Therapies organized the first scientific workshop on CAR T-cell toxicities during the annual society meeting. The workshop functioned to (1) aggregate reports of CAR T-cell emergent toxicities, including movement disorders after B-cell maturation antigen CAR T cell, coagulation abnormalities, and prolonged cytopenia; (2) disseminate bedside-to-bench efforts elucidating pathophysiological mechanisms of CAR T-cell toxicities, including the intestinal microbiota and systemic immune dysregulation; and (3) highlight gaps in the availability of clinical tests, such as cytokine measurements, which could be used to expand our knowledge around the monitoring of toxicities. Key themes emerged. First, although clinical manifestations may develop before the pathophysiologic mechanisms are understood, they must be studied to aid in the detection and prevention of such toxicities. Second, systemic immune dysregulation appears to be central to these emergent toxicities, and research is needed to elucidate the links between tumors, CAR T cells, and microbiota. Finally, there was a consensus around the urgency to create a repository to capture emergent CAR T-cell toxicities and the real-world management.
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    HIV-1 Nef Is Transferred from Expressing T Cells to Hepatocytic Cells through Conduits and Enhances HCV Replication
    (Public Library of Science, 2014-06-09) Park, In-Woo; Fan, Yan; Luo, Xiaoyu; Ryou, Myoung-Gwi; Liu, Jinfeng; Green, Linden; He, Johnny J.; Microbiology and Immunology, School of Medicine
    HIV-1 infection enhances HCV replication and as a consequence accelerates HCV-mediated hepatocellular carcinoma (HCC). However, the precise molecular mechanism by which this takes place is currently unknown. Our data showed that infectious HIV-1 failed to replicate in human hepatocytic cell lines. No discernible virus replication was observed, even when the cell lines transfected with HIV-1 proviral DNA were co-cultured with Jurkat T cells, indicating that the problem of liver deterioration in the co-infected patient is not due to the replication of HIV-1 in the hepatocytes of the HCV infected host. Instead, HIV-1 Nef protein was transferred from nef-expressing T cells to hepatocytic cells through conduits, wherein up to 16% (average 10%) of the cells harbored the transferred Nef, when the hepatocytic cells were co-cultured with nef-expressing Jurkat cells for 24 h. Further, Nef altered the size and numbers of lipid droplets (LD), and consistently up-regulated HCV replication by 1.5∼2.5 fold in the target subgenomic replicon cells, which is remarkable in relation to the initially indolent viral replication. Nef also dramatically augmented reactive oxygen species (ROS) production and enhanced ethanol-mediated up-regulation of HCV replication so as to accelerate HCC. Taken together, these data indicate that HIV-1 Nef is a critical element in accelerating progression of liver pathogenesis via enhancing HCV replication and coordinating modulation of key intra- and extra-cellular molecules for liver decay.
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    RNA-seq of Human T Cells after Hematopoietic Stem Cell Transplantation Identifies Linc00402 as a Regulator of T-Cell Alloimmunity
    (American Association for the Advancement of Science, 2021) Peltier, Daniel; Radosevich, Molly; Ravikumar, Visweswaran; Pitchiaya, Sethuramasundaram; Decoville, Thomas; Wood, Sherri C.; Hou, Guoqing; Zajac, Cynthia; Oravecz-Wilson, Katherine; Sokol, David; Henig, Israel; Wu, Julia; Kim, Stephanie; Taylor, Austin; Fujiwara, Hideaki; Sun, Yaping; Rao, Arvind; Chinnaiyan, Arul M.; Goldstein, Daniel R.; Reddy, Pavan; Pediatrics, School of Medicine
    Mechanisms governing allogeneic T cell responses after solid organ and allogeneic hematopoietic stem cell transplantation (HSCT) are incompletely understood. To identify lncRNAs that regulate human donor T cells after clinical HSCT, we performed RNA sequencing on T cells from healthy individuals and donor T cells from three different groups of HSCT recipients that differed in their degree of major histocompatibility complex (MHC) mismatch. We found that lncRNA differential expression was greatest in T cells after MHC-mismatched HSCT relative to T cells after either MHC-matched or autologous HSCT. Differential expression was validated in an independent patient cohort and in mixed lymphocyte reactions using ex vivo healthy human T cells. We identified Linc00402, an uncharacterized lncRNA, among the lncRNAs differentially expressed between the mismatched unrelated and matched unrelated donor T cells. We found that Linc00402 was conserved and exhibited an 88-fold increase in human T cells relative to all other samples in the FANTOM5 database. Linc00402 was also increased in donor T cells from patients who underwent allogeneic cardiac transplantation and in murine T cells. Linc00402 was reduced in patients who subsequently developed acute graft-versus-host disease. Linc00402 enhanced the activity of ERK1 and ERK2, increased FOS nuclear accumulation, and augmented expression of interleukin-2 and Egr-1 after T cell receptor engagement. Functionally, Linc00402 augmented the T cell proliferative response to an allogeneic stimulus but not to a nominal ovalbumin peptide antigen or polyclonal anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a regulator of allogeneic T cell function.