IL-4-DEFICIENT BALB C MICE RESIST INFECTION WITH LEISHMANIA-MAJOR/

Mice with a genetically engineered deficiency for either IL-4 or IFN-g amma R1 (single mutants), and IL-4/IFN-gamma R1 (double mutants) on th e Balb/c and 129Sv background were used to study the course of infecti on with Leishmania major. In contrast to genetically resistant 129Sv w ild-type mice, IL-4/IFN-gamma R1 double mutant mice developed fatal di sease with parasite dissemination to visceral organs similar to mice l acking IFN-gamma R1 only. Balb/c mice, which are exquisitely susceptib le to L. major, were rendered resistant to infection by disruption of the IL-4 gene. As compared to homozygous IL-4(+/+) mice, heterozygous IL-4(+/-) animals consistently developed smaller lesions with less ulc eration and necrosis, indicating the likelihood of gene-dosage effects . This implicates that the magnitude of the IL-4 response determines t he severity of disease. CD4(+) T cells of IL-4-deficient mice showed i mpaired Th2 cell development, as assessed by quantitative RT-PCR of ch aracteristic cytokines. Development of resistance is not explained by default Th1 development, because this was observed only at very late s tages of infection. Moreover, the induction of inflammatory cytokines (e.g., IL-1 alpha, IL-1 beta, TNF-alpha, IL-12) together with iNOS in the lesion and draining lymph nodes was not altered in the absence of IL-4.