Sialoadhesin-positive host macrophages play an essential role in graft-versus-leukemia reactivity in mice

We recently established an effective immune T-cell-mediated graft-versus-le ukemia (GVL) murine model system in which complete tumor remissions were ac hievable even in advanced metastasized cancer. We now describe that this T- cell-mediated therapy is dependent on host macrophages expressing the lymph ocyte adhesion molecule sialoadhesin (Sn). Depletion of Kupffer cells in tu mor-bearing mice during adoptive immunotherapy (ADI) or the treatment of th ese animals with anti-Sn monoclonal antibodies led to complete or partial i nhibition of the immune T-cell-mediated therapeutic effect. Furthermore, Sn + host macrophages in livers formed clusters during ADI with donor CD8 T ce lls. To test for a possible antigen presentation function of these macropha ges, we used as an in vitro model the antigen beta-galactosidase for which a dominant major histocompatibility complex (MHC) class I L-d-restricted pe ptide epitope is known to be recognized by specific CD8 cytotoxic T lymphoc ytes (CTL), We demonstrate that purified Sn+ macrophages can process exogen ous beta-galactosidase and stimulate MHC class I peptide-restricted CTL res ponses. Thus, Sn+ macrophages, which are significantly increased in the liv er after ADI, may process tumor-derived proteins via the MHC class I pathwa y as well as via the MHC class II pathway, as shown previously, and present respective peptide epitopes to CD8 as well as to CD4 immune T cells, respe ctively. The synergistic interactions observed before between immune CD4 an d CD8 T cells during ADI could thus occur in the observed clusters with Sn host macrophages. (C) 1999 by The American Society of Hematology.