Mechanisms of activation of alloimmune memory cells by immunologically nonspecific signals were investigated utilizing the mitogenic oxidizing agents, neuraminidase and galactose oxidase (NAGO) and sodium periodate (IO4 -). Direct activation of primary long-term human mixed-lymphocyte culture (MLC) cells (memory cells) with either NAGO or IO4 - resulted in increased specific secondary cytolytic activity. Kinetics of the proliferative and cytotoxic responses resulting from such treatment of memory cells paralleled those resulting from treatment of memory cells with irradiated cells that were the stimulators in the primary MLC. Indirect activation of memory cells by NAGO or IO4 --treated and irradiated syngeneic cells also resulted in increased specific secondary cytolytic activity. In contrast, peripheral blood mononuclear cells (PBM) activated by the mitogenic oxidizing agents did not develop cytolytic activity toward syngeneic or multiple allogeneic target cells, despite extensive proliferative responses. Cytotoxicity generated by either direct or indirect activation of memory cells by IO4 - was prevented by treatment of the oxidized cells with the reducing agent, sodium borohydride. Incubation of memory cells in supernatants from 24-hr cultures of PBM activated with either NAGO or IO4 - resulted in proliferation and in an increase in cytolytic activity in memory cells, but not in PBM. These findings indicate that alloimmune memory cells can be activated by immunologically nonspecific lymphocyte-derived signals that do not depend on alloantigen or lectin.
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