IL-4-and IL-4 receptor-deficient BALB/c mice reveal differences in susceptibility to Leishmania major parasite substrains

Using genetically pure BALB/c mice deficient in IL-4 (IL-4(-/-)) or IL-4 re ceptor cu-chain (IL-4R alpha(-/-)), we have observed different disease outc omes to Leishmania major infection depending on the parasite substrain, Inf ection with L. major LV39 caused progressive, nonhealing ulcers and uncontr olled parasite growth in both IL-4(-/-) and IL-4Ra(-/-) mice, In contrast, infection with L, major IR173 was partially controlled in IL-4(-/-) mice bu t efficiently controlled in IL-4R alpha(-/-) mice. Both IL-4(-/-) and IL-4R alpha(-/-) mice infected with either substrain displayed reduced Th2 respo nses. Surprisingly, IFN-gamma secretion was not up-regulated in the mutant mice, even in the IL-4R alpha(-/-) mice, which were resistant to L, major I R173. The lack of increased IFN-gamma production suggests that cytokine cro ss-regulation may not be operating in this model and that the effective rat ios of Th1/Th2 cytokines become more indicative of disease outcome. The par tial vs complete resistance to IR173 in IL-4(-/-) or IL-4R alpha(-/-) mice implies that, in addition to IL-4, IL-13 may be involved in disease progres sion during L, major infection. The results with LV39 infection indicate th at yet another unidentified factor is capable of causing susceptibility to L. major in the absence of IL-4 or IL-4 signaling.