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From the Cancer Research Campaign Laboratories,*
the
Beatson Institute for Cancer Research, Bearsden, Glasgow, Scotland; the
Academic Transfusion Medicine Unit,§
Department
of Medicine, University of Glasgow, Glasgow Royal Infirmary, Glasgow,
Scotland; the Department of Pathology,¶
University
of Glasgow, Glasgow, Scotland; the Departments of
Dermatology
and
Pathology,||
University of Vienna, Vienna, Austria;
Novartis Forschunginstitut,**
Vienna, Austria;
and Leukosite Incorporated,
Cambridge, Massachusetts
The lymphatic vessels (lymphatics) play an important role in
channeling fluid and leukocytes from the tissues to the secondary
lymphoid organs. In addition to driving leukocyte egress from
blood, chemokines have been suggested to contribute to
leukocyte recirculation via the lymphatics. Previously, we have
demonstrated that binding sites for several pro-inflammatory
ß-chemokines are found on the endothelial cells (ECs) of lymphatics
in human dermis. Here, using the MIP-1
isoform
MIP-1P, we have extended these studies to further support
the contention that the in situ chemokine binding to
afferent lymphatics exhibits specificity akin to that observed
in vitro with the promiscuous ß-chemokine receptor D6.
We have generated monoclonal antibodies to human D6 and showed D6
immunoreactivity on the ECs lining afferent lymphatics,
confirmed as such by staining serial skin sections with antibodies
against podoplanin, a known lymphatic EC marker. In
parallel, in situ hybridization on skin with
antisense D6 probes demonstrated the expression of D6 mRNA by lymphatic
ECs. D6-immunoreactive lymphatics were also abundant in mucosa and
submucosa of small and large intestine and appendix, but not
observed in several other organs tested. In lymph nodes, D6
immunoreactivity was present on the afferent lymphatics and also in
subcapsular and medullary sinuses. Tonsilar lymphatic sinuses were also
D6-positive. Peripheral blood cells and the ECs of blood vessels and
high endothelial venules were consistently nonreactive with anti-D6
antibodies. Additionally, we have demonstrated that D6
immunoreactivity is detectable in some malignant vascular tumors
suggesting they may be derived from, or phenotypically similar
to, lymphatic ECs. This is the first demonstration of chemokine
receptor expression by lymphatic ECs, and suggests that D6 may
influence the chemokine-driven recirculation of leukocytes through the
lymphatics and modify the putative chemokine effects on the development
and growth of vascular tumors.
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