Cell-mediated immune response in experimental visceral leishmaniasis. I. Correlation between resistance to Leishmania donovani and lymphokine-generating capacity
To define the conditions under which mononuclear phagocytes display microbicidal activity against the intracellular amastigote form of Leishmania donovani (LD), we examined the interaction of this protozoan with three diverse populations of mouse peritoneal macrophages. Although capable of killing the hemoflagellate (promastigote) form of LD, normal resident cells exerted no activity against amastigotes. Surprisingly, amastigotes also readily survived within macrophages activated in vivo by pretreatment with C. parvum or systemic infection with BCG, T. gondii, or LD. In contrast, once activated in vitro by antigen- or mitogen-stimulated lymphokines, resident cells killed 90% of ingested amastigotes. To explore the role of these macrophage-activating lymphokines in an in vivo model of visceral leishmaniasis, genetically susceptible (BALB/c) and resistant (DBA/2J) mice were challenged i.v. with 1 x 107 LD amastigotes. During the next 8 to 12 wk, the course of visceral infection was examined in parallel with spleen cell capacity to proliferate in response to mitogen and to generate active mitogen- and antigen-induced lymphokines. DBA/2J mice permitted minimal visceral LD replication, and spleen cells remained fully responsive in both assays. In contrast, amastigotes rapidly proliferated within liver and spleen macrophages of BALB/c mice during the first 4 wk, at which time spleen cell activities were strikingly suppressed. After 8 wk, however, these animals acquired sufficient resistance to inhibit amastigote replication and reduce visceral burdens by up to 80%. These in vivo events were closely paralleled by recovery of spleen cell proliferative and lymphokine-generating capacities. The early inhibition of BALB/c spleen cell responses was associated with the presence of splenic suppressor cells whose activity was detectable after 2 wk of infection but not at 12 wk. These results demonstrate that lymphocyte activity correlates with both the establishment and the resolution of experimental visceral leishmaniasis, and indicate that the ability to generate macrophage-activating lymphokines is a key determinant of acquired cellular resistance to LD infection.