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* Rheumatology Unit, Guy’s, King’s and St. Thomas’, School of Medicine, London, United Kingdom;
Department of General and Vascular Surgery, Guy’s and St. Thomas’ Hospital Trust, St. Thomas’ Hospital, London, United Kingdom;
MediCity Research Laboratory, University of Turku, Turku, Finland;
BHF Cardiovascular Medicine Unit, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, London, United Kingdom; and
¶ Department of Biochemical Pharmacology, William Harvey Research Institute, Charterhouse Square, London, United Kingdom
Stromal cell-derived factor 1 (SDF-1; CXCL12), a CXC chemokine, has
a primary role in signaling the recruitment of hemopoietic stem cell
precursors to the bone marrow during embryonic development. In
postnatal life, SDF-1 is widely expressed and is induced in chronically
inflamed tissues such as psoriatic skin and the rheumatoid synovium,
but has also been implicated in the migration of lymphocytes to
lymphoid organs. To investigate the role of SDF-1 in recirculation and
homing in vivo, we have developed a model in which human peripheral
lymph nodes (huPLN) are transplanted into SCID mice. We have shown that
huPLN transplants are viable, vascularized by the murine circulation
that forms functional anastomoses with transplant vessels. In addition,
grafts retain some features of the pretransplantation tissue, such as
lymphoid follicles, lymphatic and high endothelial venule markers. We
also show that SDF-1 is capable of inducing the migration of a
SDF-1-responsive cell line (U937) and human PBLs from the murine
circulation into the grafts in a dose-dependant manner, inhibitable by
CXCR4 blockade. The mechanism of action of SDF-1 in this model is
independent from that of TNF-
and does not rely on the up-regulation
of adhesion molecules (such as ICAM-1) on the graft vascular
endothelium. This is the first description of huPLN transplantation
into SCID mice and of the functional effects of SDF-1 in regard to the
migration of human cells into huPLN in vivo. This model provides a
powerful tool to investigate the pathways involved in cell migration
into lymphoid organs and potentially to target them for therapeutic
purposes.
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