Browsing by Author "Tran, Hien"

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    Modeling BK Virus Infection in Renal Transplant Recipients.
    (Viruses, 2024-12) Myers, Nicholas; Droz, Dana; Rogers, Bruce W; Tran, Hien; Flores, Kevin B; Chan, Cliburn; Knechtle, Stuart J; Jackson, Annette M; Luo, Xunrong; Chambers, Eileen T; McCarthy, Janice M
    Kidney transplant recipients require a lifelong protocol of immunosuppressive therapy to prevent graft rejection. However, these same medications leave them susceptible to opportunistic infections. One pathogen of particular concern is human polyomavirus 1, also known as BK virus (BKPyV). This virus attacks kidney tubule epithelial cells and is a direct threat to the health of the graft. Current standard of care in BK virus-infected transplant recipients is reduction in immunosuppressant therapy, to allow the patient's immune system to control the virus. This requires a delicate balance; immune suppression must be strong enough to prevent rejection, yet weak enough to allow viral clearance. We seek to model viral and immune dynamics with the ultimate goal of applying optimal control methods to this problem. In this paper, we begin with a previously published model and make simplifying assumptions that reduce the number of parameters from 20 to 14. We calibrate our model using newly available patient data and a detailed sensitivity analysis. Numerical results for multiple patients are given to show that the newer model reflects observed dynamics well.
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    The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease.
    (J Clin Invest, 2010-01) Na, Il-Kang; Lu, Sydney X; Yim, Nury L; Goldberg, Gabrielle L; Tsai, Jennifer; Rao, Uttam; Smith, Odette M; King, Christopher G; Suh, David; Hirschhorn-Cymerman, Daniel; Palomba, Lia; Penack, Olaf; Holland, Amanda M; Jenq, Robert R; Ghosh, Arnab; Tran, Hien; Merghoub, Taha; Liu, Chen; Sempowski, Gregory D; Ventevogel, Melissa; Beauchemin, Nicole; van den Brink, Marcel RM
    Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits alphaE and beta7, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8-like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.