Susceptibility or resistance to Leishmania infection is dictated by the macrophages evolved under the influence of IL-3 or GM-CSF

Although enhanced monocytopoiesis is a hallmark of leishmaniasis, its signi ficance in determining the course of the disease has not been addressed. Wh ile the number of granulocyte-macrophage colony-stimulating factor (GM-CSF) -secreting cells increases in the draining lymph nodes in a resistant mouse strain (C57BL/6) during disease, in a susceptible strain (BALB/c) the numb er of interleukin-3 (IL-3)-secreting cells increases. Treatment of BALB/c m ice with anti-IL-3 antibody significantly reduces the disease score. Bone m arrow macrophages derived under stimulation with IL-3 (IL-3-M Phi) or GM-CS F (GM-M Phi) differ functionally. GM-M Phi are significantly more responsiv e to IFN-gamma-induced augmentation and more refractory to IL-4-mediated su ppression of anti-leishmanial activity than IL-3-M Phi LPS-induced IL-12 an d TNF-alpha secretion by both the susceptible and resistant strain-derived macrophage subsets are down-regulated. Despite down-regulation of IL-12 sec retion, GM M Phi, favor expansion of IFN-gamma-secreting cells and IL-3-M P hi favor IL-6-dependent expansion of the IL-4-secreting Th subset. Adoptive transfer of leishmanial antigen-pulsed IL-3-M Phi and GM-M Phi prior to in fection either aggravated or reduced the disease score, respectively, in BA LB/c mice. Anti-IL-6 treatment reverted the Th subset profile not only in v itro but also in vivo, resulting in a reduced disease score in both infecte d BALB/c mice and IL-3-M Phi recipients. The disease score in IL-3-M Phi re cipients is also reduced significantly after anti-IL-4 treatment.