Regulation of effector cell functions through the ligation of lymphocyte function-associated antigen-1 and intracellular adhesion molecule-1 leads to spontaneous regression of a rat histiocytoma.

Abstract

Cell adhesion molecules mediate cell-to-cell interactions, thereby regulating effective immune response against target cells. We have investigated the intercellular cross-talk between lymphocyte function-associated antigen-1 (LFA-1) and its counter-receptor, intercellular adhesion molecule-1 (ICAM-1). This interaction regulates the postadhesion events leading to the regression of a rat histiocytoma, AK-5, which is mediated by natural killer (NK) cells through antibody-dependent cell cytotoxicity (ADCC). Repeated systemic administration of anti-cell adhesion molecule (anti-CAM) monoclonal antibodies (MoAbs), i.e. anti-LFA-1 and anti-intracellular adhesion molecule-1 (anti-ICAM-1), in AK-5 tumour-bearing animals enhanced tumour growth and caused delayed regression. The immune suppression achieved after the administration of these antibodies could be attributed to the diminished cytotoxic, as well as apoptotic, activity of NK cells. The MoAbs selectively reduced the adhesion of NK cells to the tumour cells in vitro. Flow cytometric analysis showed down-regulation of Fas-ligand expression on NK and T cells following MoAb administration in vivo. Marked reduction in the lymphokine-activated killer (LAK) activity of NK cells was also observed after in vitro blocking of LFA-1 and ICAM-1 molecules. In addition, continuous MoAb administration induced suppression of the cytokine response. These results underline the importance of ligand binding between LFA-1 and ICAM-1, which could provide co-stimulation for the effector-cell functions via signalling events to induce cytotoxicity, apoptosis and cytokine production, resulting in the efficient regression of AK-5 tumour in syngeneic hosts.