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

Abstract

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 (HVG) 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 lupus-like disease in BALB/c mice injected at birth with (BALB/cxC57BL/6)F1 spleen cells. In close association with the development of tolerance to donor allografts, these mice show a polyclonal activation of F1 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 saturating doses (100 microg/2 days) of either anti-LFA-1alpha or anti-ICAM-1 mAbs, but not anti-VLA-4alpha or anti-LFA-1beta mAbs, blocks the production of anti-ssDNA autoAbs and the thrombocytopenia characteristic of this HVG disease (HVGD). However, anti-VLA-4alpha treatment is only able to delay the production of autoAbs and the anti-LFA-1beta 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.

Blocking L-selectin and α4-integrin changes donor cell homing pattern and ameliorates murine acute graft versus host disease

“…This beneficial effect of the Ab on aGVHD was not due to the depletion of donor lymphocytes, which is often seen in many tolerance induction protocols used in experimental and clinical transplantation and for the treatment of autoimmune diseases [28][29][30][31][32]. These Ab were reported as non-cytotoxic [2-4, 18,19], and we failed to detect any cytotoxic effect in a complement fixation test. Donor cells which were labeled with fluorescent dye and were treated with the Ab, could readily be detected in recipient LN and spleens.…”

Not all (cells) who wander are lost: Upstream migration as a pervasive mode of amoeboid cell motility

“…The expression of leukocyte receptors depends on the leukocyte. For example, T-cells bear the integrin α L β 2 , also known as lymphocyte function-associated antigen-1 (LFA-1), which binds intracellular adhesion molecule-1(ICAM-1), as well as α 4 β 1 , or very late antigen-4 (VLA-4), which binds vascular cell adhesion molecule-1 (VCAM-1) (López-Hoyos et al, 1999). Neutrophils bear two beta-2 integrins-LFA-1 and macrophage-1 antigen (Mac-1, α M β 2 ), which also binds to ICAM-1 (Heit et al, 2005).…”