The in vitro activation of large granular lymphocytes with recombinant interleukin-2 (rIL-2) generates a population of cytotoxic lymphocytes with broad anti-tumor reactivity. These lymphokine activated killer (LAK) cells have proven useful in the adoptive immunotherapy of metastatic tumors in animal models and man. One of the hallmarks of LAK activity is their propensity to bind and lyse virtually all types of tumor cells but not normal cells. Although LAK cells have gained much attention due to this important property, little is known about the nature of the surface structures employed by LAK cells to recognize and lyse tumor cells. Conversely, little is known about the nature of the structures on the tumor cells which stimulate LAK cell function. In this study, we propose to explore the nature of LAK recognition and activation structures by producing monoclonal antibodies (MoAbs) capable of either inhibiting or stimulating LAK cytotoxic function: specifically we plan to produce murine monoclonal antibodies generated against highly purified rat LAK cells and to screen these MoAbs for the following capabilities 1) MoAbs which block the binding of purified LAK cells to either YAC-1, P815 or MADB106 target cells; 2) MoAbs which do not block the binding, but block cytotoxicity of these same targets; 3) MoAbs which enhance cytotoxicity to these targets; and 4) MoAbs which block/enhance the proliferation of highly purified LAK cells in response to recombinant IL-2. Subsequent to the development of such MoAbs we will then analyze 1) the distribution of the various antigens among various hematopoietic cell populations (T, B, monocytes, LGL, LAK, PMN, etc), 2) the biochemical nature of the structures identified by the MoAbs and 3) For MoAbs which block target cell binding, determine the nature of the cognate ligand on the tumor cell by generating anti-idiotypic antibodies. Our preliminary data in this area provides a sufficient basis for the proposed study. Further, we feel that should this model be adequately analyzed, by the ultimate production of cDNA probes for LAK recognition structures, we will be able to quickly identify similar structures on human or mouse LAK cells for future additional studies.
