Lymphotoxin (LT), one of the first lymphokines to be discovered, was originally described as a correlate of the 24-hr inflammatory response known as delayed type hypersensitivity. Ruddle & Waksman noted that activated rat lymphocytes killed syngeneic rat embryo fibroblasts (1), due to a substance released from T lymphocytes in the presence of specific antigen (2). This phenomenon, termed" innocent bystander killing," only occurred when lymph node cells (LNC) from immunized rats were cultured in the presence of specific antigen. This induction was antigen specific; the effect on target fibroblasts was not.

Almost simultaneously, Granger and his colleagues described the pro duction of a cytotoxic factor, which they called lymphotoxin, from murine and human lymphocytes after stimulation with T cell mitogens such as phytohemagglutinin (PHA)(3). The observations were later extended to lymphocytes of several species including guinea pig and hamster. The conclusion that LT production is an in vitro correlate of delayed type hypersensitivity is based on the fact that its induction characteristics are identical to those used to define the skin test reaction (4-7). Thus, a 24-hr skin test in an animal immunized with a hapten protein conjugate is elicited only by the protein (carrier specificity). A positive skin test reaction can be transferred with cells (T cells), and there is little correlation with antibody titer. LT production is elicited, only by the carrier, from T cells from rats or mice immunized with hapten protein conjugates. LT production was not correlated with antibody production (4-7). Fur thermore, a genetic correlation existed between the ability of strains of rats to manifest strong 24-hr skin test reactions and the ability of their T cells to produce LT (4).