Mononuclear cell recruitment, granuloma assembly, and response to treatment in experimental visceral leishmaniasis: Intracellular adhesion molecule 1-dependent and -independent regulation

In experimental visceral leishmaniasis, acquired resistance to intracellula r Leishmania donovani is Th1 cell cytokine dependent and largely mediated b y gamma interferon (IFN-gamma); the same response also permits conventional antimony (Sb) chemotherapy to express its leishmanicidal effect. Since the influxing blood monocyte (which utilizes endothelial cell ICAM-1 for adhes ion and tissue entry) is a primary effector target cell for this cytokine m echanism, we tested the monocyte's role in host responsiveness to chemother apy in mice with ICAM-1 gene disruptions. Mutant animals failed to develop any early granulomatous tissue response in the liver, initially supported h igh-level visceral parasite replication, and showed no killing after Sb tre atment; the leishmanicidal response to a directly acting, alternative chemo therapeutic probe, amphotericin B, was intact. However, mutant mice proceed ed to express a compensatory, ICAM-1-independent response leading to mononu clear cell influx and granuloma assembly, control over visceral infection, and the capacity to respond to Sb, Together, these results point to the rec ruitment of emigrant monocytes and mononuclear cell granuloma formation, me diated by ICAM-1-dependent and -independent pathways, as critical determina nts of host responsiveness to conventional antileishmanial chemotherapy.