Pretreatment with recombinant Flt3 ligand partially protects against progressive cutaneous leishmaniasis in susceptible BALB/c mice

Dendritic cells are potent antigen-presenting cells that also produce inter leukin-12 (IL-12) during innate and adaptive cellular immune responses and that thereby promote the differentiation of gamma interferon (IFN-gamma)-pr oducing Th1-type CD4(+) T lymphocytes. We hypothesized that expanded dendri tic-cell populations in mice pretreated with the hematopoietic cytokine Flt 3L would protect against cutaneous Leishmania major infection. Pretreatment of disease-susceptible BALB/c mice with 10 mug of recombinant Flt3L (rFlt3 L) for 9 to 10 days before infection increased lymph node IL-12 p40 product ive capacity 20-fold compared to that of saline-injected controls, Furtherm ore, 9 of 22 (40.9%) rFlt3L-pretreated BALB/c mice resolved their cutaneous infections, whereas none of the 22 control BALB/c mice healed. Healed, rFl t3L-pretreated mice did not develop disease following reinfection. Flt3L pr etreatment also reduced parasite numbers 1,000-fold in the cutaneous lesion s at 2 weeks after infection relative to numbers in lesions of untreated co ntrols. However, Flt3L pretreatment did not significantly alter L, major-in duced IFN-gamma and IL-4 production in lymph node culture at 1, 2, and 4 we eks after infection, Despite the lack of Th immune deviation, Flt3L ligand- pretreated lymph nodes expressed up to 10-fold higher levels of IL-12 p40 a nd inducible (type 2) nitric oxide synthase mRNA at 7 days after infection. In contrast, treatment with rFlt3L after infection failed to protect again st disease despite comparable expansions of dendritic cells and IL-12 p40 p roductive capacity in both infected and uninfected BALB/c mice treated with rFlt3L, We conclude that rFlt3L pretreatment before infection with L, majo r reduces parasite load and promotes healing of cutaneous lesions without s table cytokine deviation towards a dominant Th1 cytokine phenotype.