Immunoregulation in visceral leishmaniasis

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

DESCRIPTION: Unlike mice infected with Leishmania major, which exhibit either self-healing or progressive disease, which correlates with the development of dominant Th1 versus Th2 type responses, mice infected with Leishmania donovanigenerally develop Th1 type responses and control visceral parasites. Still, strains of mice, which exhibit similar patterns of acute susceptibility to infection, may heal at dramatically different rates as evidenced by the fact that C57BL/6 mice exerting rapid control of visceral parasites while BALB/c mice develop persistent infections. We have shown that both BALB/c and, to a lesser extent, C57BL/6 mice which lack the gene for IL-10 are highly resistant to acute infection and that both strains of IL-10 deficient mice rapidly eliminate visceral parasites. These studies implicate IL-10 as an important cytokine, which regulates the development of resistance during visceral disease. We have also shown that mice, which lack the gene for CD28, an important co-stimulatory molecule involved in T cell activation, are also highly resistant to infection with L. donovani. In this proposal, we will examine the role of IL-10 during infection by identifying the source of IL-10 producing cells and how IL-10 production by macrophages or T cells may exert regulatory controls on the development of resistance. In particular, we will focus on how the presence or absence of IL-10 production by parasitized macrophages alters macrophage microbicidal function and ask whether IL-10 plays a critical role in regulating the production of cytokines such as IL-12, IFN-gamma and TNF-alpha, which are critical to the development of a protective Th1 type response. We will also examine whether the absence of CD28 alters the immune response to L. donovani, or whether secondary defects which are observed in CD28-/- mice such as a diminished capacity to produce antibody can alter signals provided to macrophages by opsonized parasites, leading to different patterns of pro-inflammatory (1L012) or anti-inflammatory (IL-10) cytokine production.