Immunostimulation by retinoic acid

Retinoids have been shown to inhibit tumour growth in several model systems. In this paper evidence that immune effectors are important for this effect is discussed. Injection of retinoic acid (RA) into mice before challenge with allogeneic or syngeneic tumour cells results in a strong increase in cell-mediated cytotoxicity specific for the respective tumour. This stimulation appears to be due to effects taking place before or during the induction phase rather than the effector phase of cell-mediated cytolysis. The effector cells responsible for cytotoxicity express the Thy 1 antigen, are H-2 specific and are therefore T killer cells. The induction of T cell-mediated cytotoxicity requires the participation of the lymphokine interleukin 2 (IL-2). The possibility was tested that RA directly or indirectly influences the production of IL-2 and thereby stimulates the induction of T killer cells. Results indeed show that RA-injected mice display an increased capacity to produce IL-2 upon stimulation of their splenocytes in a mixed lymphocyte reaction. It appears therefore that RA has an effect on T cells that are destined to produce IL-2 upon antigenic challenge. Since IL-2 plays a role not only in the induction of specific cytotoxic T cells but also in the induction of natural killer (NK) cells, RA was also tested in a model system in which NK cells appear to play an important protective role. Results showed that split-dose irradiated mice that lose their NK activity and subsequently develop leukaemia can be protected from leukaemogenesis either by reconstitution with NK cells or by injection with RA. The question of whether this effect is due to stimulation of immune effectors or is a direct effect on the preleukaemic cells is discussed.