Parallel inheritance of tissue catalase activity and immunostimulatory action of amphotericin B in inbred mouse strains

Abstract

Both amphotericin B (AmB) and its methyl ester derivative are potent immunoadjuvants that also stimulate murine B lymphocytes and macrophages in vitro. Most of the common inbred mouse strains show AmB-induced immunostimulation (AmB-high responders) but mice from the C57BL strains, regardless of H-2 genotype, are AmB-low responders. Lymphoid cells from AmB-high responder strains also exhibit greater resistance to H2O2 toxicity in vitro compared with cells from AmB-low responders. This result led to an evaluation of differences in the tissue catalase levels of AmB-high and -low responder strains. Results from several laboratories, including ours, indicate that C57BL mouse strains express low levels of tissue catalase activity in addition to low or absent immunostimulant effects of AmB. Several AmB-high responder strains have high spleen cell, macrophage, and liver catalase, and the mouse strain distribution of enzyme activity as well as the dominant inheritance of the low catalase phenotype is compatible with regulation by the Ce-1 locus in lymphoid organs as well as liver. Other evidence also suggests that H2O2 metabolism is important in lymphoid cell responses to AmB. For example, AmB stimulates a stronger respiratory burst in macrophages from AmB-high responder strains under the same conditions that inhibit burst activity in macrophages from low responders. Selective immune enhancement by AmB in high catalase mouse strains along with enhanced susceptibility to AmB toxicity in low responder C57BL mice with low tissue catalase activity suggests that cellular peroxidation is a major determinant of the genetic regulation of amphotericin-induced immunostimulation.