B-cell lymphomas (formerly called reticulum cell sarcomas [RCS]) which develop spontaneously in SJL/J strain mice promote their own growth by stimulating proliferation of autochthonous CD4 cells, which secrete lymphokines required by the tumor cells. In the course of determining that the efficacy of cyclophosphamide (Cy) treatment of tumor-bearing SJL/J mice was derived primarily from effects on the host nonmalignant lymphoid system rather than from direct effects on tumor cells, we uncovered a novel chemo/immunotherapeutic mechanism, a better understanding of which could aid in the development of more effective means of treating analogous human lymphomas. Preliminary data indicate that the markedly increased survival of tumor-bearing mice obtained through Cy administration (107 RCS5 tumor cells day-1, 100mg/kg of Cy ip, day 0 = RCS[Cy] treatment) can be attributed primarily to: 1) the generation of a CD8+ population specifically suppressive of the SJL/J-lymphoma-stimulated proliferation of syngeneic CD4 cells, and; 2) the preferential Cy-mediated elimination of CD4 cells able to proliferate in response to SJL/J lymphomas. The objective of the ensuing proposal is to obtain a better understanding of the mechanisms by which the RCS[Cy} treatment proves to be efficacious. More specifically, we wish to: 1) define the signals which lead to the generation of CD8 cells, specifically suppressive of the tumor-stimulated MLR; 2) determine how these cell function and what they recognize, and; 3) whether they are mono-or pauci- clonal based on T-cell receptor usage. WE also wish to determine the mechanism, free of CD8-suppressor-cell influences, by which the CD4 cell population in RCS[Cy]-treated mice becomes functionally deficient in CD4 cells that proliferate in response to SJL/J lymphomas. Our study of the role of specific CD8 suppressor cells in this system is based upon the hypothesis that the specificity of suppressor cells resides in recognition by their TCRs of idiotypic determinants on the T-cells they are capable of suppressing. This hypothesis is consistent with basic immunologic tenets. Should this theory by found applicable in our system, preparation of monoclonal antiidiotypic antibodies to the TCRs of clones of specific CD8 suppressors may yield reagents of potential therapeutic value able to regulate the function of specific CD8 suppressor cell clones. Based on idiotypic network theory, these same reagents may be reactive with the still elusive determinants on SJL/J lymphomas which stimulate the syngeneic CD4-cell proliferation which is so vital to tumor growth.
| Luo, H; Sopchak, L; Lerman, S P et al. (1995) Selective loss of H-2Ds antigen on a murine B lymphoma due to a post-transcriptional block in expression. Mol Immunol 32:1011-20 |
| Wrone-Smith, T; Cankovic, M; VanBuren, E et al. (1993) Cyclophosphamide treatment of an SJL murine B-cell lymphoma increases the proportion of suppressive CD8+ over tumor-stimulatory CD4+ T-lymphocytes. Leuk Res 17:967-75 |
| Sopchak, L; Thrush, G R; Lerman, S P et al. (1991) Loss of myb expression in an aggressive SJL/J B-cell lymphoma. Oncogene 6:1335-8 |
