Gene therapy to target dendritic cells from blood to lymph nodes.
Peripheral lymph nodes (PLN) are strategic microenvironments where antigen-presenting dendritic cells (DC), loaded with environmental antigens, and naive lymphocytes meet to initiate immune responses. The unique capacity of DC to induce primary immune responses has led to their use in clinical medicine; however, delivering DC to lymph nodes is problematic. Intravenously injected DC cannot access to PLN, while DC injected into tissue migrate inefficiently through lymphatics to PLN. We achieved DC targeting to T-cell areas of PLN by endowing DC with a novel receptor for peripheral node addressin (PNAd), an adhesion molecule present on the lymph node venular endothelium. This novel receptor is a chimeric E/L-selectin (ELS) that, we have previously shown, binds to PNAd. DC were genetically modified by retroviral transduction to express ELS. ELS expression was targeted to tips of microvilli, and mediated rolling of DC on PNAd both in vivo and in vitro. Such genetically engineered DC could extravasate directly from blood through the lymph node endothelium as opposed to nontransduced DC. This study provides evidence that the trafficking of DC can be modified using gene transfer technologies. More efficient delivery of DC to PLN should assist the development of improved vaccination strategies.
Robert
C
C
Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, MA, USA.
Klein
C
C
Cheng
G
G
Kogan
A
A
Mulligan
R C
RC
von Andrian
U H
UH
Kupper
T S
TS
D019264:Adoptive Transfer / Q000379:methods*; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D019040:E-Selectin / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D019041:L-Selectin / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology*; D008565:Membrane Proteins; D016253:Microscopy, Immunoelectron; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods
D000954:Antigens, Surface; D019040:E-Selectin; C069886:L-selectin counter-receptors; D008565:Membrane Proteins; D019041:L-Selectin