A. Molina et al., PREVENTION OF MERCURIC CHLORIDE-INDUCED NEPHRITIS IN THE BROWN-NORWAYRAT BY TREATMENT WITH ANTIBODIES AGAINST THE ALPHA-4 INTEGRIN, The Journal of immunology, 153(5), 1994, pp. 2313-2320
HgCl2 induces the synthesis of anti-GBM Abs with the development of gl
omerular and interstitial nephritis, as well as proteinuria, in the Br
own Norway rat. The development of this autoimmune disease is a conseq
uence of the appearance of an autoreactive T cell subset-inducing acti
vation of B cells. The administration to mercury-treated rats of the m
ouse anti-human VLA alpha 4 HP2/1 mAb, which cross-reacts with the rat
homologue integrin, completely abrogated the interstitial cell infilt
rates. As demonstrated by peripheral blood analysis, this effect is-no
t a result of the depletion of circulating leukocytes or leukocyte sub
sets. Interestingly, the administration of Abs specific for the alpha
4 integrin also highly reduced anti-GBM Ab synthesis, thus preventing
detectable glomerular deposits and proteinuria. Our results confirm th
at in vivo alpha 4 functions in adhesive interaction of circulating le
ukocytes and vascular endothelium, and is centrally important in the e
xtravasation and migration of T lymphocytes to sites of tissue injury.
We also found a complete absence of interstitial cell infiltrates, to
gether with a positive glomerular IgG lineal deposition pattern, when
anti-GBM Abs were passively transferred to rats pretreated with anti-a
lpha 4 mAb, thus indicating an independent role of alpha 4 integrin in
both extravasation of immune cells and production of autoantibodies.
Furthermore, these in vivo findings provide preliminary evidence for t
he participation of the VLA-4 integrin in mediating the intercellular
interaction of leukocytes regulating the production of Abs, most likel
y through the existence of additional yet unknown ligand(s).