Natural and Expanded CD4 +CD25 + Regulatory T Cells in Bone Marrow Transplantation

Division of Blood and Marrow Transplantation, Stanford University, Stanford, California 94305, USA.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation (Impact Factor: 3.4). 01/2011; 17(1 Suppl):S58-62. DOI: 10.1016/j.bbmt.2010.10.020
Source: PubMed
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    • "Distinct populations of regulatory T cells are capable of controlling immune reactions such as CD4 + CD25 + Foxp3 + natural T reg (Fontenot et al., 2003; Sakaguchi et al., 2008). Adoptive transfer of T reg suppresses GVHD in allogeneic animal models of HCT and in humans (Brunstein et al., 2011; Colonna et al., 2011; Di Ianni et al., 2011; Edinger et al., 2003; Nguyen et al., 2008). The goal of our study was to evaluate these clinically utilized strategies to promote the engraftment of undifferentiated and differentiated ESCs. "
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    ABSTRACT: Embryonic stem cells (ESCs) hold promise for the treatment of many medical conditions; however, their utility is limited by immune rejection. The objective of our study is to establish tolerance or promote engraftment of transplanted ESCs as well as mature cell populations derived from ESCs. Luciferase (luc(+))-expressing ESCs were utilized to monitor the survival of the ESCs and differentiated progeny in living recipients. Allogeneic recipients conditioned with fractioned total lymphoid irradiation (TLI) and anti-thymocyte serum (ATS) or TLI plus regulatory T cells (Treg) promoted engraftment of ESC allografts after transplantation. Following these treatments, the engraftment of transplanted terminally differentiated endothelial cells derived from ESCs was also significantly enhanced. Our findings provide clinically translatable strategies of inducing tolerance to adoptively transferred ESCs for cell replacement therapy of medical disorders. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(11). DOI:10.1016/j.celrep.2015.02.050 · 8.36 Impact Factor
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    • "IL-10, TGF-β), and inhibitory molecules (i.e. CTLA-4 and PD-1) involved in controlling the proliferation and activation of alloreactive T cells have been identified and found to play important roles in GVHD pathophysiology [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. "
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    ABSTRACT: Lag-3 has emerged as an important molecule in T cell biology. We investigated the role of Lag-3 in conventional T cell (Tcon) and regulatory T cell (Treg) function in murine GVHD with the hypothesis that Lag-3 engagement diminishes alloreactive T cell responses after bone marrow transplantation. We demonstrate that Lag-3 deficient Tcon (Lag-3(-/-) Tcon) induce significantly more severe GVHD than wild type (WT) Tcon and that the absence of Lag-3 on CD4 but not CD8 T cells is responsible for exacerbating GVHD. Lag-3(-/-) Tcon exhibited increased activation and proliferation as indicated by CFSE and bioluminescence imaging analyses and higher levels of activation markers such as CD69, CD107a, granzyme B, and Ki-67 as well as production of IL-10 and IFN-g early after transplantation. Lag-3(-/-) Tcon were less responsive to suppression by WT Treg as compared to WT Tcon. The absence of Lag-3, however, did not impair Treg function as both Lag-3(-/-) and WT Treg equally suppress the proliferation of Tcon in vitro and in vivo and protect against GVHD. Further, we demonstrate that allogeneic Treg acquire recipient MHC class II molecules through a process termed trogocytosis. As MHC class II is a ligand for Lag-3, we propose a novel suppression mechanism employed by Treg involving the acquisition of host MHC-II followed by the engagement of Lag-3 on T cells. These studies demonstrate for the first time the biologic function of Lag-3 expression on conventional and regulatory T cells in GVHD and identify Lag-3 as an important regulatory molecule involved in alloreactive T cell proliferation and activation after bone marrow transplantation.
    PLoS ONE 01/2014; 9(1):e86551. DOI:10.1371/journal.pone.0086551 · 3.23 Impact Factor
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    ABSTRACT: Template-matching is the least sophisticated and most compute-intensive part of automatic target recognition (ATR) processing for synthetic aperture radar (SAR) applications. Complexity considerations dictate the use of low template densities in target signature space, while the extreme sensitivity of correlation processing to pose mandates the averaging of templates over a range of pose angles to achieve some generalization. Thus, the templates considered in ATR systems are often generated by noncoherently averaging target templates within a five degree pose-angle window, resulting in poor correlation gain. In this paper, we propose to dramatically increase the computational efficiency of correlation-based reasoning, using a completely different paradigm-the bit-ordered tree classifier (BOTC)-to enable high-density, high-confidence matching. Instead of performing, for example, 8-bit correlation between template and test images and comparing to a threshold, the BOTC makes selected binary comparisons to reach the same acceptance/rejection decisions with comparable operational characteristics, using far fewer computations. We report up to a two orders of magnitude speedup, compared to 8-bit correlation in preliminary testing on SAR target data from the MSTAR collection. We also investigate the efficient mapping of our novel BOTC technique to adaptive computing platforms such as field programmable gate arrays (FPGAs).
    Signals, Systems & Computers, 1997. Conference Record of the Thirty-First Asilomar Conference on; 12/1997
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