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The cellular infiltrate in xenografts suggests that macrophages may be involved in xenograft rejection. However, the precise role of macrophages in xenograft rejection has not yet been fully addressed.Xenogeneic rat skin grafts were transplanted to macrophage colony stimulating factor (M-CSF)/macrophage-deficient osteopetrotic ([OP]−/−) and wild-type control mice. Skin graft survival and antidonor rat humoral responses were quantified.Xenogeneic rat skin grafts survived 13 days in wild-type control mice, survival of rat skin grafts was significantly prolonged to 24 days in [OP]−/− mice (P < 0.01). Similar results were observed in sensitized [OP]−/− and control mouse recipients, showing markedly prolonged rat skin graft survival in [OP]−/− mice. Levels of T-cell-dependent antirat antibodies [immunoglobulin G (IgG)2a and IgG3] in sera of [OP]−/− mice were significantly lower than that of control mice 2 weeks post-rat skin grafting. The proliferative responses to xenogeneic rats not to allogeneic mouse stimulation of T cells from [OP]−/− mice were significantly lower than that of wild-type mice. However, neutrilization of M-CSF by anti-M-CSF monoclonal antibody (mAb) or the addition of M-CSF to the in vitro culture systems of wild-type or [OP]−/− mouse T-responder cells, respectively, did not significantly change proliferative responses and cytolytic function against xenogeneic rat targets of wild-type or [OP]−/− mouse T-responder cells.The in vitro data indicate that M-CSF does not directly regulate cellular immune responses to xenoantigens. The present studies indicate that macrophages may play an important role in immune rejection of xenografts. The precise role of macrophages in xenograft rejection should be further investigated.