jueves, 14 de agosto de 2014

Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis

Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis



Sci Transl Med
Vol. 6, Issue 249, p. 249ra109 
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3009377
  • RESEARCH ARTICLE
CELL THERAPY

Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis

  1. Biju Parekkadan5,6,*,
+Author Affiliations
  1. 1Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  2. 2Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
  3. 3Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
  4. 4School of Immunity and Infection, University of Birmingham, Birmingham B15 2TT, UK.
  5. 5Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, Boston, MA 02114, USA.
  6. 6Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
+Author Notes
  •  These authors contributed equally to this work.
  •  Present address: Department of Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
  1. *Corresponding author. E-mail: biju_parekkadan@hms.harvard.edu (B.P.); turley.shannon@gene.com (S.J.T.);a.fletcher@bham.ac.uk (A.L.F.)

    Abstract

    Sepsis is an aggressive inflammatory syndrome and a global health burden estimated to kill 7.3 million people annually. Single-target molecular therapies have not addressed the multiple disease pathways triggered by septic injury. Cell therapies might offer a broader set of mechanisms of action that benefit complex, multifocal disease processes. We describe a population of immune-specialized myofibroblasts derived from lymph node tissue, termed fibroblastic reticular cells (FRCs). Because FRCs have an immunoregulatory function in lymph nodes, we hypothesized that ex vivo–expanded FRCs would control inflammation when administered therapeutically. Indeed, a single injection of ex vivo–expanded allogeneic FRCs reduced mortality in mouse models of sepsis when administered at early or late time points after septic onset. Mice treated with FRCs exhibited lower local and systemic concentrations of proinflammatory cytokines and reduced bacteremia. When administered 4 hours after induction of lipopolysaccharide endotoxemia, or cecal ligation and puncture (CLP) sepsis in mice, FRCs reduced deaths by at least 70%. When administered late in disease (16 hours after CLP), FRCs still conveyed a robust survival advantage (44% survival compared to 0% for controls). FRC therapy was dependent on the metabolic activity of nitric oxide synthase 2 (NOS2) as the primary molecular mechanism of drug action in the mice. Together, these data describe a new anti-inflammatory cell type and provide preclinical evidence for therapeutic efficacy in severe sepsis that warrants further translational study.
    Citation: A. L. Fletcher, J. S. Elman, J. Astarita, R. Murray, N. Saeidi, J. D’Rozario, K. Knoblich, F. D. Brown, F. A. Schildberg, J. M. Nieves, T. S. Heng, R. L. Boyd, S. J. Turley, B. Parekkadan, Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis. Sci. Transl. Med. 6249ra109 (2014).


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