Interleukin‐4 transgenic mice of resistant background are susceptible to Leishmania major infection

Abstract

The outcome of cutaneous leishmaniasis is dependent on the balance of Th1 and Th2 cells. In the murine model, Th1 cells are host-protective whereas the Th2 cells are disease-promoting. However, the in vivo role of interleukin-4 (IL-4), a signature product of Th2 cells, is uncertain. We compared the course of Leishmania major infection in the genetically resistant 129/Sv mice and the mutant 129/Sv mice transgenic for the murine IL-4 gene under the control of the immunoglobulin heavy chain enhancer and promoter. We report here that in contrast to their wild-type parents, the IL-4 transgenic mice are susceptible to L. major infection. This is associated with the development of inexorably progressive lesions and parasite loads. Spleen cells from infected transgenic mice produced significantly higher levels of IL-4 but lower amounts of interferon-gamma when stimulated in vitro with leishmanial antigens compared to those from infected normal 129/Sv mice. Furthermore, sera from the infected transgenic mice contained higher levels of IL-4 and IgE than the sera of infected normal 129/Sv mice. These results, therefore, establish in a new animal model that IL-4 promotes disease development in murine cutaneous leishmaniasis.

Th1‐Th2 Cytokine Kinetics in the Bronchoalveolar Lavage Fluid of Mice Infected with Cryptococcus neoformans of Different Virulences

“…The type of mouse used in our experiments has been previously shown to develop microorganism-dependent dominant Th cytokines secretion; Th 1 dominant immunity in leishmaniasis (25) and Th2 in allergic aspergillosis (22,23). Thus, the same host may show alternate Th cytokine response to different organisms or organisms with different virulence.…”

Comparative immune study on cutaneous leishmaniasis patients with single and multiple sores

“…Alexander and Russell (1992) also showed that IFN-c plays a critical role in the activation of macrophages to kill intracellular parasites by inducing production of NO which is critical for elimination of parasites. IFN-c production is to a large extent induced by IL-12 and down-regulated by IL-4 (Leal et al 1993;SchartonKesten et al 1995) the resistant hosts mount a Th-1 response (high IFN-c low IL-4) whereas in susceptible hosts a Th-2 response (low IFN-c high IL-4) predominates (Locksley and Scott 1991). Scott et al (1991) and Wang et al (1994) revealed in their studies that depletion of IFN-c leads to a Th-2 response with disseminating disease in healer mice, while Sadick et al (1990) and Chatelain et al (1992) showed that depletion of IL-4 leads to a Th-1 response and allows no healer mice to cure the infection.…”

What about Th1/Th2 in cutaneous leishmaniasis vaccine discovery?

“…Thus, targeted disruption of the IFN-γ gene in C57BL/6 mice causes these animals, which are otherwise resistant to infection with L. major, to become highly susceptible to these organisms (15,16). Moreover, IL-4 transgenic resistant mice expressing low levels of this cytokine fail to clear the infection (17,18). In addition, targeted disruption of the IL-4 gene in BALB/c mice causes these animals, which are otherwise susceptible to infection with L. major, to become highly resistant to these organisms (19).…”