Therapy with a combination of low doses of interleukin 12 and chloroquine completely cures blood-stage malaria, prevents severe anemia, and induces immunity to reinfection

The immunoregulatory cytokine interleukin 12 (IL-12) induces host resistanc e against experimental malaria. In this study, we tested the feasibility of using IL-12 in combination with chloroquine (CQ) to rescue susceptible A/J mice from lethal blood-stage Plasmodium chabaudi AS infection. Combined tr eatment with low doses of CQ and IL-12 resulted in a >15-fold reduction in the parasite load and 100% survival of A/J mice with established infections . Compared to control mice, which succumbed to severe anemia, CQ-plus-IL-12 -treated mice had significantly higher early- and late-stage erythroid-cell progenitors in the bone marrow and spleen, resulting in significantly high er hematocrits, erythrocyte counts, and percentages of reticulocytes. Produ ction of parasite-specific gamma interferon (IFN-gamma) by splenocytes from these mice was upregulated >20-fold relative to controls in parallel with enhanced IFN-gamma mRNA expression. Further, enhanced responsiveness to IL- 12 and increased downstream IFN-gamma production in CQ-plus-IL-12-treated m ice was evident from increased mRNA expression for the beta 1 and beta 2 su bunits of IL-12 receptor in the splenocytes. Moreover, this combined therap y induced higher levels of anti-malaria antibodies than did CQ alone as wel l as sterile immunity against reinfection. Because IL-12 can be used at low doses and is effective even in established infections, it may be feasible to use this immunochemotherapeutic approach in human malaria.