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 sp ecific immune responses. They are used for homing, cell migration, cell-cel l contact and, in some cases,for the delivery of costimulatory signals. Sin ce the host-versus-graft (HVC) reaction represents a particular form of T-B -cell interaction, we have explored whether the inhibition of lymphocyte fu nction-associated antigen-1/intracellular adhesion molecule-1 (LFA-1/ICAM-1 ) interactions and the signalling through very late activation antigen-4 (V LA-4) have any effect on the development of a lupuslike disease in BALB/c m ice injected at birth with (BALB/c x C57BL/6)F-1 spleen cells. In close ass ociation 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 th e development of a mild glomerulonephritis. The dose of the monoclonal anti body (mAb) employed has been adjusted to block completely the molecule on t he 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 an ti-LFA-1 beta mAbs, blocks the production of anti-ssDNA autoabs and the thr ombocytapenia characteristic of this HVG disease (HVGD). However, anti-VLA- 4 alpha treatment is only able to delay the production of autoAbs and the a nti-LFA-1 beta treatment, not to modify the evolution of the HVGD. These re sults point to the relevance of LFA-1/ICAM-1 interactions, but not of the V LA-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.