RT Journal Article
SR Electronic
T1 Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 249ra109
OP 249ra109
DO 10.1126/scitranslmed.3009377
VO 6
IS 249
A1 Fletcher, Anne L.
A1 Elman, Jessica S.
A1 Astarita, Jillian
A1 Murray, Ryan
A1 Saeidi, Nima
A1 D’Rozario, Joshua
A1 Knoblich, Konstantin
A1 Brown, Flavian D.
A1 Schildberg, Frank A.
A1 Nieves, Janice M.
A1 Heng, Tracy S. P.
A1 Boyd, Richard L.
A1 Turley, Shannon J.
A1 Parekkadan, Biju
YR 2014
UL http://stm.sciencemag.org/content/6/249/249ra109.abstract
AB 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.