title: Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis.
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.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia. School of Immunity and Infection, University of Birmingham, Birmingham B15 2TT, UK. biju_parekkadan@hms.harvard.edu turley.shannon@gene.com a.fletcher@bham.ac.uk.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Fletcher
authors.affiliation: Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, Boston, MA 02114, USA.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Elman
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: Astarita
authors.affiliation: Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, Boston, MA 02114, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Murray
authors.affiliation: Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, Boston, MA 02114, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Saeidi
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Joshua
authors.initials: J
authors.lastname: D'Rozario
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Knoblich
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Flavian D
authors.initials: FD
authors.lastname: Brown
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Schildberg
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Nieves
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Tracy S P
authors.initials: TS
authors.lastname: Heng
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Boyd
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. biju_parekkadan@hms.harvard.edu turley.shannon@gene.com a.fletcher@bham.ac.uk.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Turley
authors.affiliation: Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, Boston, MA 02114, USA. Harvard Stem Cell Institute, Cambridge, MA 02138, USA. biju_parekkadan@hms.harvard.edu turley.shannon@gene.com a.fletcher@bham.ac.uk.
authors.forename: Biju
authors.initials: B
authors.lastname: Parekkadan
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000473:pathology; D002432:Cecum / Q000473:pathology; D002465:Cell Movement; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000473:pathology / Q000628:therapy; D005260:Female; D005347:Fibroblasts / Q000637:transplantation*; D008026:Ligation; D008070:Lipopolysaccharides; D008198:Lymph Nodes / Q000166:cytology*; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010537:Peritoneum / Q000473:pathology; D011677:Punctures; D018805:Sepsis / Q000473:pathology / Q000628:therapy*; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse