Effects of retinoic acid on the immune system: stimulation of T killer cell induction.

Retinoic acid (RA), a vitamin A derivative with anti-tumor activity, was assayed for its effects on the immune system in mice. High doses of this compound (1000 microgram/mouse/day) have toxic effects and cause depletion on the peripheral lymphoid organs (spleen, thymus) while leaving the bone marrow cells unaffected. Both the in vivo and in vitro induction of cell-mediated cytotoxicity (CMC) to allogeneic tumor cells is stimulated at least tenfold by low doses (25--300 microgram/mouse/day) of RA while high doses suppress CMC induction. RA is shown to be a specific adjuvant for the induction of cytotoxic thymus-derived lymphocytes (T cells) and not a general T cell mitogen or adjuvant. It does not enhance the proliferative response in the mixed lymphocyte culture nor does it stimulate lymphocyte proliferation in response to the mitogens concanavalin A and phytohemagglutinin. The induction of cooperating T cells and the delayed-type hypersensitivity reaction are also not stimulated by RA. In contrast to the reported stimulatory effects of retinyl palmitate and retinyl acetate, RA does not stimulate the humoral response to erythrocytes. The strong adjuvant effects that RA has on the induction of CMC at low doses may be responsible for its anti-tumor activity.