Mechanism of action of 15-deoxyspergualin. I. Suppressive effect on the induction of alloreactive secondary cytotoxic T lymphocytes in vivo and in vitro.

The effects of 15-deoxyspergualin (DSG) and its derivative deoxymethylspergualin (MeDSG), which is more stable than DSG in solution, on the induction of alloreactive secondary cytotoxic T lymphocytes (CTL) in mice in vivo and in vitro were determined. Secondary CTL were generated in vivo or in vitro by injecting mice with mitomycin C (MMC)-treated allogenic tumour cells twice with a 1-week interval or by culturing spleen cells of alloantigen-primed mice with MMC-treated allogenic mouse spleen cells, respectively. DSG preferentially suppressed the generation of secondary CTL at the differentiation but not at the effector phase. DSG also suppressed the responsiveness of spleen cells to secondary antigen in a non-specific manner. MeDSG suppressed the in vitro induction of secondary CTL in a dose-dependent manner; however, it did not suppress the activity of CTL already induced. The inhibitory effect of MeDSG on CTL induction was totally abolished by exogenous recombinant murine interferon-gamma (IFN-gamma) and partly by interleukin-2 (IL-2), suggesting that suppressive mechanisms of MeDSG (DSG) may be mainly mediated by the inability of lymphocytes to produce IFN-gamma or by impairment of an unknown cascade(s) reconstituted by IFN-gamma.