CYCLOPHOSPHAMIDE PLUS TUMOR-NECROSIS-FACTOR-ALPHA CHEMOIMMUNOTHERAPY CURED MICE - LIFELONG IMMUNITY AND REJECTION OF RE-IMPLANTED PRIMARY LYMPHOMA

Changes in functionally and phenotypically definable splenocyte subset s in aging mice which had been rendered tumor-free in early life by im munochemotherapy (cyclophosphamide plus tumor necrosis factor-alpha) w ere studied in the syngeneic EL4 lymphoma-C57BL/6 murine model. Treatm ent-induced longterm survivors (LTS) surviving rechallenge are termed ''immune-LTS''. On day 120 (day 0, initial tumor inoculation), splenoc ytes from day 60 rechallenged immune-LTS developed significantly great er specific anti-EL4 cytolytic activity in an ex vitro assay than thos e from non-rechallenged LTS. Splenocytes from combination-treated grou ps developed significantly higher activity than those from cyclophosph amide-induced immune-LTS. The splenic effector precursor was a CD8(+) T cell. The specific anti-EL4 effector cell from the cyclophosphamide- induced immune-LTS was CD4(-) CD8(+); however, approximately 50% of th ose from combination-treated immune-LTS appeared to be CD4(+)CD8(+). O n day 520 immune-LTS were randomized into 2 groups. One group was re-i mplanted with EL4 tumor; all mice survived. The other group was killed and, even though their splenocytes developed considerable anti-EL4 ac tivity, their allogeneic responsiveness was as reduced as that of age- matched controls. Phenotypic analysis, compared with splenocytes from young and age-matched controls, revealed changes in the makeup of each T-cell subset, except the CD4(+)CD8(+), and all subsets, except the C D4(-)CD8(-), had increases in CD44 positivity. On day 625, the age of these mice was equivalent to the median life-span of C57BL/6 mice; nev ertheless, their splenocytes developed high anti-EL4 activity. Phenoty pic analysis indicated that, compared to day 520, there was a major de crease in CD4(-)CD8(+) splenocytes; we suggest that these cells had mi grated to the site of tumor eradication. (C) 1995 Wiley-Liss, Inc.