Lymphokine-activated killer cells in rats: analysis of tissue and strain distribution, ontogeny, and target specificity

Abstract

The coculture of lymphoid cells from Fischer 344 rats with recombinant human interleukin 2 (rIL-2) resulted in the generation of lymphokine-activated killer (LAK) cells. Maximal LAK activity was obtained between 200 and 1000 units/ml rIL-2. Lymphoid cells from spleen, thymus, bone marrow, peripheral blood, and lymph nodes were able to generate LAK activity although the kinetics and magnitudes of the responses were appreciably different among these tissues. Thus, while spleen and blood lymphocytes responded quickly (by day 3) and gave the highest level of LAK activity in response to rIL-2, bone marrow and thymus cells responded only by 7 to 9 days in culture. LAK activity could be generated from a variety of rat strains regardless of whether there were high or low levels of endogenous splenic natural killer (NK) activity, but the early (day 3) response was lower in the strains with low levels of NK activity. Cells with LAK activity could lyse a variety of tumor targets including fresh ascites or fresh syngeneic solid tumor explants but could not lyse fresh normal cells including syngeneic fibroblasts, peripheral blood lymphocytes, bone marrow cells, thymocytes, or T,B blasts. The generation of LAK activity required a concomitant proliferative response and could be completely abrogated by mitomycin C, actinomycin D, or X-irradiation above 500 rads. These treatments, however, did not affect natural killer activity or short-term (4 h) IL-2-boosted NK activity. LAK activity could be generated from spleen cells obtained from rats as early as 10 days of age but could not be generated from unfractionated neonatal spleen, neonatal liver, or peritoneal macrophages. The ontogeny of the development of splenic LAK activity correlated closely to the development of concurrent natural killer activity. When mixed with an NK-resistant mammary adenocarcinoma (MADB106) and adoptively transferred to normal syngeneic recipients in standard Winn-type assays, LAK cells were effective at inducing complete tumor inhibition.