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Cyclophosphamide plus tumor necrosis factor‐α chemoimmunotherapy cured mice: Life‐long immunity and rejection of re‐implanted primary lymphoma
Author(s) -
Ehrke M. Jane,
Verstovšek Srdan,
Krawczyk Christian M.,
Ujházy Peter,
Zaleskis Gintaras,
Maccubbin Darbie L.,
Mihich Enrico
Publication year - 1995
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910630327
Subject(s) - cd8 , splenocyte , immune system , cyclophosphamide , immunology , tumor necrosis factor alpha , t cell , biology , medicine , chemotherapy
Changes in functionally and phenotypically definable spleno‐cyte subsets in aging mice which had been rendered tumor‐free in early life by immunochemotherapy (cyclophosphamide plus tumor necrosis factor‐α) were studied in the syngeneic EL4 lymphoma‐C57BL/6 murine model. Treatment‐induced long‐term survivors (LTS) surviving rechallenge are termed “immune‐LTS”. On day 120 (day 0, initial tumor inoculation), splenocytes from day 60 rechallenged immune‐LTS developed significantly greater specific anti‐EL4 cytolytic activity in an ex vitro assay than those from non‐rechallenged LTS. Splenocytes from combination‐treated groups developed significantly higher activity than those from cyclophosphamide‐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 those from combination‐treated immune‐LTS appeared to be CD4 + CD8 + . On day 520 immune‐LTS were randomized into 2 groups. One group was re‐implanted with EL4 tumor; all mice survived. The other group was killed and, even though their splenocytes developed considerable anti‐EL4 activity, 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 CD4 − 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; nevertheless, their splenocytes developed high anti‐EL4 activity. Phenotypic analysis indicated that, compared to day 520, there was a major decrease in CD4 − CD8 + splenocytes; we suggest that these cells had migrated to the site of tumor eradication.