LEISHMANIA-MAJOR - DIFFERENTIAL RESISTANCE TO INFECTION IN C57BL 6 (HIGH INTERFERON-ALPHA/BETA) AND CONGENIC B6.C-H-28(C) (LOW INTERFERON-ALPHA/BETA) MICE/

In murine cutaneous leishmaniasis caused by Leishmania major (Lm), res istance often associates with the outgrowth of Lm-specific Th1 cells. Parasites are eliminated by Th1-mediated activation of infected macrop hages (MO) which destroy Lm by producing toxic nitrogen and oxygen rad icals. The cytokine IFN-alpha activates microbicidal functions of MOs and facilitates outgrowth of Th1 cells. Therefore, we compared the cou rse of infection with Lm in resistant C57BL/6 mice, bearing the If-1(h ) high expression allele for IFN-alpha/beta, with the congenic B6.C-H- 28(c) mouse, bearing the If-1(l) low expression allele from the Lm-sus ceptible BALB/c strain. We observed that B6.C-H-28(c) animals develope d up to 70% larger footpad lesions and harbored up to 1000-fold more p arasites than C57BL/6 mice. Furthermore, peak Lm-specific IFN-gamma pr oduction in the B6.C-H-28(c) animals was lower and delayed by approxim ate to 2 weeks, whereas IL-4 production was higher and persisted appro ximate to 2 weeks longer. Since these results suggested that IFN-alpha /beta plays a protective role in mice infected with Lm, we determined whether infusing B6.C-H-28(c) mice with IFN-alpha would influence the course of infection with Lm. Unfortunately, the mice developed severe peritoneal hemorrhaging in response to injection with IFN-alpha. There fore, we examined the ability of IFN-alpha to activate MOs to destroy Lm in vitro. We observed that rIFN-alpha could synergize with subactiv ating doses of LPS to activate both C57BL/6 and BALB/c peritoneal MOs to produce NO and to kill intracellular Lm. Taken as a whole, these re sults suggest that type I interferons may play a protective role in cu taneous leishmaniasis. (C) 1996 Academic Press, Inc.