The mononuclear phagocyte system is an important element in the host's defenses against neoplasia but is not always effective, as the host is not always able to concentrate and appropriately modulate mononuclear phagocytes at sites of neoplastic cells. The effective accumulation of mononuclear phagocytes within tumors and their activation for cytolytic function are controlled by a complex interplay of signals from host, environment and tumor. Murine macrophages develop activation by interacting with multiple signals and by passing through stages characterized by objective markers. Human monocytes can also be activated for cytolysis, and such activated mononuclear cells can be identified. The specific molecular signals that induce activation and regulate the activated state are being defined. In particular, murine and human neoplasms contain and release low-molecular-weight factors, reactive with monoclonal antibodies against the retrovirus envelope protein P15E, that inhibit the chemotaxis and accumulation of mononuclear phagocytes. We hypothesize that the complex activation path usually seen can be altered or deranged in tumor-bearing hosts, perhaps by such low molecular weight factors. We are testing this hypothesis in mice and humans. Using objective, functional, enzymatic and antigenic markers of the stages of activation, we are defining the signals regulating the stages of activation. We are studying the activational path for normal human monocytes, whether discrete stages of such activation exist and, if so, how these stages are marked. We will determine in mice and in humans how tumors alter the accumulation and activation of mononuclear phagocytes by release of soluble regulatory products and the nature and source of these products. Emphasis is placed on delineating the cell biology of the induction and the expression of activation in order to elucidate the fundamental regulatory physiology of macrophage activation.