Presence of a macrophage-mediated suppressor cell mechanism during cell-mediated immune response in experimental visceral leishmaniasis.

In susceptible BALB/c mice, systemic intracellular infection with Leishmania donovani provokes generation of adherent spleen cells which can suppress both mitogen- and specific-antigen-stimulated T-cell responses. To characterize the responsible suppressor cell, we irradiated (2,000 R) adherent spleen cells from L. donovani-infected mice or treated them with anti-Thy-1.2 antibody plus complement. Neither anti-T-cell treatment diminished the capacity to inhibit lymphocyte proliferative activity. In addition, as judged by morphologic and functional criteria, 80 to 90% of the adherent cells appeared to be macrophages. Four observations suggested an immunopathogenic role for these suppressor macrophages. (i) Their appearance and disappearance paralleled the establishment and resolution of L. donovani visceral infection in vivo. (ii) Suppressive effects included inhibition of production of the macrophage-activating lymphokine gamma interferon (IFN-gamma). (iii) On transfer into immune mice, suppressor macrophages impaired naturally acquired resistance to L. donovani. (iv) Inhibition of macrophage prostaglandin metabolism by indomethacin reduced suppressor activity in vitro and resulted in a 50% decrease in parasite visceral replication in vivo. In addition, prophylactic cyclophosphamide treatment inhibited the development of suppressor macrophages, and under these conditions visceral infection was rapidly controlled. These results suggested that disseminated L. donovani infection provokes a macrophage-mediated suppressor mechanism which appears to contribute to establishment of visceral leishmaniasis in a susceptible host.