Mononuclear Cell Recruitment, Granuloma Assembly, and Response to Treatment in Experimental Visceral Leishmaniasis: Intracellular Adhesion Molecule 1-Dependent and -Independent Regulation

Abstract

In experimental visceral leishmaniasis, acquired resistance to intracellular Leishmania donovani is Th1 cell cytokine dependent and largely mediated by gamma interferon (IFN-␥); 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 adhesion and tissue entry) is a primary effector target cell for this cytokine mechanism, we tested the monocyte's role in host responsiveness to chemotherapy in mice with ICAM-1 gene disruptions. Mutant animals failed to develop any early granulomatous tissue response in the liver, initially supported high-level visceral parasite replication, and showed no killing after Sb treatment; the leishmanicidal response to a directly acting, alternative chemotherapeutic probe, amphotericin B, was intact. However, mutant mice proceeded to express a compensatory, ICAM-1-independent response leading to mononuclear cell influx and granuloma assembly, control over visceral infection, and the capacity to respond to Sb. Together, these results point to the recruitment of emigrant monocytes and mononuclear cell granuloma formation, mediated by ICAM-1-dependent and -independent pathways, as critical determinants of host responsiveness to conventional antileishmanial chemotherapy.

Intercellular Adhesion Molecule 1 Deficiency Leads to Impaired Recruitment of T Lymphocytes and Enhanced Host Susceptibility to Infection withTrypanosoma cruzi

“…Furthermore, it may indicate that although ICAM-1 is required for cell migration, the activated cell trafficking to and through the cardiac vascular endothelium during T. cruzi-elicited myocarditis could be mediated by ICAM-1-independent pathways, as previously described in other models (44,45). Supporting this possibility, the cell migration into the cardiac tissue was only partially abrogated (34 -51%) when activated blood leukocytes from T. cruzi-infected wild-type mice were adoptively transferred to infected ICAM-1 KO mice.…”

“…The presence of inflammatory cells in the cardiac tissue of ICAM-1-deficient mice on day 25 postinfection could be due to compensatory mechanisms of cellular migration, as observed in mice infected with visceral leishmaniasis and disseminated candidiasis (44,45). Furthermore, it may indicate that although ICAM-1 is required for cell migration, the activated cell trafficking to and through the cardiac vascular endothelium during T. cruzi-elicited myocarditis could be mediated by ICAM-1-independent pathways, as previously described in other models (44,45).…”

Accelerated Control of VisceralLeishmania donovaniInfection in Interleukin-6-Deficient Mice

“…The inflammatory response at liver foci parasitized by L. donovani culminates in granuloma assembly (26,31). In IL-6 Ϫ/Ϫ mice, mononuclear-cell influx with the encircling of infected Kupffer cells was rapid and considerably more prominent than in WT mice (Fig.…”

“…As anticipated with the C57BL/6 background (32), WT animals also proceeded to convert initial susceptibility to the self-healing phenotype. In this model, the latter is dependent on a Th1-cell-type response and is mediated by IFN-␥-stimulated mononuclear-cell influx, macrophage activation, and induction of intracellular parasite killing (25,26,32,39).…”

“…The histologic response to the infection was evaluated microscopically in liver sections stained with hematoxylin and eosin. The number of granulomas (infected Kupffer cells which had attracted Ն5 mononuclear cells [26,31]) was counted in 100 consecutive 40ϫ fields, and at 100 parasitized foci, the granulomatous reaction was scored as none, developing, or mature (31). Mature granulomas show a core of fused, parasitized Kupffer cells, numerous surrounding mononuclear cells, and epithelioid-cell-type changes (28).…”