SPECIFIC ANTI-EL4-LYMPHOMA IMMUNITY IN MICE CURED 2 YEARS EARLIER WITH DOXORUBICIN AND INTERLEUKIN-2

This laboratory has reported the conditions for an effective, non-toxi c, chemoimmunotherapy utilizing doxorubicin in combination with prolon ged administration of interleukin-2 and the identification of the crit ical role of activated CD8+ T cells in the therapeutic effect. Mice (C 57BL/6) cured in those studies have been followed for the remainder of their life spans. These mice, approximately 2 months of age when init ially inoculated with syngeneic EL4 lymphoma, survived for more than 2 years, the normal life span of C57BL/6 mice. Mice 4 months old reinoc ulated with the EL4 cells all survived. At about 1 year of age mice we re sacrificed and the ability of their thymocytes and splenocytes to d evelop specific CD8+ anti-EL4 activity was as high as it had been at t he time of tumor rejection. At about 2 years of age EIA was reimplante d into mice; all of them survived. These surviving mice, at 2 years 2 months of age, as well as a group of 2-year-old mice not rechallenged, were killed and functional antitumor activity and phenotype character istics of various lymphocyte populations were determined in comparison to those of young and age-matched control mice. The phenotyping of th e lymphocytes from the cured mice indicated very notable differences i n subset distribution and increased CD44 expression. Functionally they developed high levels of anti-EL4 activity, which was ablated by comb ined treatment with monoclonal antibodies against CD8 and CD44, indica ting the role of memory cells. Consistent with cells from aged mice, t hese same cell populations had a very reduced allogeneic responsivenes s. It appears that cured mice have developed an immune memory specific for EL4.