Interpretation of lymphocytotoxicity assays and the demonstration of auto-tumor reactive lymphocytes in patients: central issues of present day tumor immunology.

The outcome of a short term cell-mediated cytotoxic assay depends on the susceptibility of the target and the activation profile of the lymphocyte population. Certain cultured cell lines are highly sensitive to the lytic effect of lymphocytes of unimmunized donors, provided they have been derived from the same species--NK effect. This cytotoxicity seems to be independent of lymphocyte receptor-target antigen interaction but is likely due to some membrane property of the target. Specificity is only on the species level. With fresh, non-cultured targets, in certain systems which operationally conform with the natural killing henomenon, antigen specific recognition defines the effect. We propose that on fresh targets, the operational NK effect, should be viewed fundamentally similar to CTL. Analysis of antigen induced cytotoxic systems suggests that the question of "specificity" on the effector level can only be asked if target cells of similar characteristics are used. Specificity at the effector level depends on the panel of targets presented. Cells with inherent sensitivity to the lytic effect of activated lymphocytes (i.e. NK sensitive cells) may be killed even if they are unrelated to the stimulus, and also such NK resistant cells which carry antigens for which the relevant receptor carrying lymphocytes are present in a sufficient number. Lysis of the latter cells can occur due to transactivation. Transactivation means that accompanying the event of antigen specific recognition in a lymphocyte population, additional cells are activated that do not participate in the specific reaction. In patients with solid tumors lymphocytes which recognize autologous tumor biopsy cells and can damage them, have been demonstrated. Auto-tumor-killer lymphocytes have been generated in conventional mixed lymphocyte cultures, using the patient's lymphocytes as responders--probably due to transactivation or in mixed lymphocyte cultures containing lymphocytes and autologous tumor cells.