Different roles for LFA-1 and VLA-4 integrins in T-B-cell interactions in vivo

Adhesion molecules are critical in the cellular interactions involved in specific immune responses. They are used for homing, cell migration, cell-cell contact and, in some cases,for the delivery of costimulatory signals. Since the host-versus-graft (HVC) reaction represents a particular form of T-B-cell interaction, we have explored whether the inhibition of lymphocyte function-associated antigen-1/intracellular adhesion molecule-1 (LFA-1/ICAM-1) interactions and the signalling through very late activation antigen-4 (VLA-4) have any effect on the development of a lupuslike disease in BALB/c mice injected at birth with (BALB/c x C57BL/6)F-1 spleen cells. In close association with the development of tolerance to donor allografts, these mice show a polyclonal activation of F-1 donor B cells by alloreactive host CD4(+) T cells, manifested by the production of autoantibodies (autoAbs) and the development of a mild glomerulonephritis. The dose of the monoclonal antibody (mAb) employed has been adjusted to block completely the molecule on the surface of peripheral lymphocytes without interfering with the induction of neonatal tolerance. Injection of satarating doses (100 mu g/2 days) of either anti-LFA-1 alpha or anti-ICAM-1 mAbs, but not anti-VLA-4 alpha or anti-LFA-1 beta mAbs, blocks the production of anti-ssDNA autoabs and the thrombocytapenia characteristic of this HVG disease (HVGD). However, anti-VLA-4 alpha treatment is only able to delay the production of autoAbs and the anti-LFA-1 beta treatment, not to modify the evolution of the HVGD. These results point to the relevance of LFA-1/ICAM-1 interactions, but not of the VLA-4-mediated signal, in the polyclonal B-cell activation occurring during the allogeneic interactions between host T helper type 2 cells and donor B cells in HVGD.