RECOMBINANT INTERLEUKIN-12 ENHANCES CELLULAR IMMUNE-RESPONSES TO VACCINATION ONLY AFTER A PERIOD OF SUPPRESSION

Adjuvant use of recombinant murine IL-12 (rmIL-12) was examined in mic e vaccinated with irradiated syngeneic tumor or allogeneic cells. rmIL -12 given to A/J mice vaccinated with irradiated SCK tumor cells engin eered to secrete granulocyte/macrophage-colony-stimulating factor resu lted in significantly better protection from tumor challenges 28 days after vaccination but, unexpectedly, severely compromised host protect ion 14 days after vaccination. Immune suppression was rmIL-12 dose dep endent and manifested as reduced splenic CTL activity, stimulated cyto kine release and ability to reject SCK cells. Transient immune suppres sion was also seen with rmIL-12 given during vaccination of C3H/HeN mi ce with irradiated K1735 melanoma cells and of C57BL/6 mice with irrad iated allogeneic HKB cells. The period of suppression coincided with t ransiently reduced splenic T-cell mitogenic responses to concanavalin A and IL-2, suggesting that they may be causally related, Suppression appears to be due to impaired immune effector mechanisms rather than i mpaired host immunization, which is actually enhanced as evidenced by the enhanced reaction to immunogens when hosts are challenged later af ter rmIL-12 administration, Demonstration that rmIL-12, as it is frequ ently used, induces a transient period of impaired immune response tha t can compromise host protection suggests that the unquestioned effect iveness of rmIL-12 against murine tumors is primarily due to activatio n of mechanisms other than antigen-specific tumor immunity (e.g., anti angiogenic effects) and that use of human IL-12 should be monitored fo r similar effects.