Cellular basis of immunologic interactions in adoptive T cell therapy of established metastases from a syngeneic murine XXXX .

@entity1619 @entity242 @entity2047 @entity5 @entity1961 @entity3 @entity3414
The adoptive transfer of specifically sensitized T lymphocytes can effectively mediate the regression of established local and @entity3 . Previous experiments using the weakly immunogenic MCA 105 @entity242 indicated that cellular interactions between transferred @entity1961 + helper and @entity3414 + cytotoxic immune T cells were necessary for mediating @entity5 regression. In this study, the kinetics of @entity1619 cell interactions were analyzed by in vivo depletion of T cell subsets with mAb. The anti- @entity5 efficacy of transferred immune cells was abrogated by in vivo administration of either @entity1961 or @entity3414 mAb on the day of cellular therapy. However, if mAb were given 3 days after the transfer of immune cells, depletion of @entity3414 + but not @entity1961 + cells abrogated anti- @entity5 efficacy. T cell depletion on day 6 after transfer of immune cells had no adverse effect on @entity5 regression, indicating the period required for T cell reactivity in vivo. Furthermore, depletion of Ia+ cells by in vivo mAb treatment abrogated the anti- @entity5 efficacy of immune cells. It is thus hypothesized that there are two distinct but sequential phases of in vivo T cell interactions leading to the regression of established @entity5 after adoptive immunotherapy. An initial "helper/inducer" phase apparently requires the interaction of @entity1961 + immune cells and the @entity5 Ag involving Ia+ cells. The inducement of @entity1961 + cell activation is to provide helper function via the secretion of @entity2047 . The second phase designated as an "effector phase" involves differentiation of immune @entity3414 + cells under the influence of @entity2047 secreted during the helper/inducer phase for generation of mature @entity3414 + effector cells. To further support the hypothesis of a two-phase process we have examined the phenotype and kinetics of @entity5 regression mediated by effector cells generated by secondary in vitro sensitization (IVS). Although the IVS cells were generated from fresh MCA 105 immune spleen cells, their anti- @entity5 efficacy was mediated solely by @entity3414 + lymphocytes. Kinetic studies revealed that the in vivo requirement of IVS @entity3414 + effector cells to mediate @entity5 regression was less than 3 days, and the anti- @entity5 reactivity of these cells was not affected by in vivo depletion of Ia+ cells. Thus, the IVS reaction is likely representative of the in vivo counterpart of the helper/inducer phase leading to the generation of mature @entity3414 + immune effector cells. Tumor regression after transfer of @entity3414 + cells generated in IVS therefore required a relatively shorter period of time than that required after the transfer of fresh noncultured MCA 105 immune spleen cells.
