CD44 EXPRESSION BY LEUKOCYTES IN RHEUMATOID-ARTHRITIS AND MODULATION BY SPECIFIC ANTIBODY - IMPLICATIONS FOR LYMPHOCYTE ADHESION TO ENDOTHELIAL-CELLS AND SYNOVIOCYTES IN-VITRO
Fr. Brennan et al., CD44 EXPRESSION BY LEUKOCYTES IN RHEUMATOID-ARTHRITIS AND MODULATION BY SPECIFIC ANTIBODY - IMPLICATIONS FOR LYMPHOCYTE ADHESION TO ENDOTHELIAL-CELLS AND SYNOVIOCYTES IN-VITRO, Scandinavian journal of immunology, 45(2), 1997, pp. 213-220
Anti-CD44 MoAb IM7 induced the loss of CD44 from mouse leucocytes ther
eby inhibiting leucocyte migration and joint inflammation in murine ar
thritis. Thus, targeting CD44 with MoAb may have potential for the tre
atment of patients with inflammatory joint diseases. Expression of CD4
4 by peripheral blood (PB) and synovial fluid (SF) leucocytes from rhe
umatoid arthritis (RA) patients was compared and the ability of IM7 to
modulate this expression determined. RASF lymphocytes showed increase
d CD44 expression compared with those in PB indicative of an activated
phenotype, As inflammatory SF did not up-regulate CD44 expression on
PB lymphocytes, the increased CD44 expression by SF lymphocytes was a
result of the selective homing of CD44(high) cells to the synovium rat
her than an effect of the synovial environment. RASF granulocytes show
ed reduced CD44 expression compared with those in PB, again indicative
of an activated phenotype. However, this reduction could be induced o
n PB granulocytes following culture with inflammatory SF and was inhib
ited by anti-TNF-or MoAb, implying that soluble factors in inflammator
y SF such as TNF-alpha induced granulocyte activation and CD44 loss. I
M7 induced the loss of CD44 from lymphocytes (both from PB and SF) and
granulocytes in vitro, but was subsequently re-expressed after 24 h c
ulture in the absence of the MoAb, This loss of CD44 was blocked by se
rine- and metalloprotease inhibitors implying that IM7 induced the pro
teolytic cleavage of CD44 by a mechanism similar to that reported for
the loss of CD44 from PMA-activated granulocytes. Furthermore, IM7-tre
ated CD44(low) lymphocytes showed reduced adherence to both an endothe
lial cell line and RA synovial fibroblasts in vitro. The unique abilit
y of IM7 to reduce CD44 expression by lymphocytes suggests that it cou
ld prevent lymphocyte extravasation and synovial infiltration in RA as
previously reported in murine arthritis.