The course of infection with the protozoan parasite Leishmania is determined in part by their early replication in macrophages, the exclusive host cells for these organisms. Although factors contributing to the survival of Leishmania are not well understood, cytokines influence the course of infection. Transforming growth factor-beta (TGF-beta) is a multipotential cytokine with diverse effects on cells of the immune system, including down-regulation of certain macrophage functions. Leishmanial infection induced the production of active TGF-beta, both in vitro and in vivo. TGF-beta was important for determining in vivo susceptibility to experimental leishmanial infection.

Transforming growth factor I8 (TGF-1) has potent down-regulating effects on macrophages and is thus capable of influencing the fate of intramacrophage parasites, including leishmanias. We report the development of a mouse model for the study of the human pathogen Leishmania braziliensis and demonstrate, both in vitro and in vivo, a key regulatory role for TGF-fi in the pathogenesis of infection with this parasite. Recombinant TGF-fi added to cultures of murine peritoneal macrophages led to increased intracellular L. braziliensis replication, whereas addition of neutralizing anti-TGF-fi monoclonal antibody decreased levels of infection.Macrophages infected with L. braziliensis produced biologically active TGF-(3, with a direct correlation between amounts of TGF-13 induced by two parasite isolates and their relative virulence. In vivo, treatment with recombinant TGF-fi rendered avirulent parasites virulent and activated latent L. braziliensis infection. Activation of parasite replication was observed in mice which had been infected with L. braziliensis 15 weeks previously but had not developed lesions or had healed lesions, depending on the parasite isolate used to infect the mice. The exacerbation of L. braziliensis infection in vivo was associated with an increase of interleukin 10 mRNA in the draining lymph node. These results demonstrate that TGF-13 is able to alter the course of in vitro and in vivo infections with L.

IL-10 has been shown to inhibit some aspects of macrophage activation, including the in vitro IFN-gamma-mediated intracellular killing of the protozoan parasite Trypanosoma cruzi. We have previously shown that genetically susceptible mice produced more IL-10 during T. cruzi infection than resistant mice, suggesting an association between IL-10 production and disease susceptibility. In the present study, such an association was documented. IL-10 mRNA was present in the spleens of susceptible C57BL/6 mice, but not in resistant (C57BL/6 x DBA/2) F1 mice, as early as 2 days after infection with T. cruzi. In susceptible mice, IL-10 mRNA was found in enriched populations of splenic T cells and peritoneal macrophages by 4 days after infection. By 14 days after infection, IL-10 mRNA was detected in enriched populations of splenic T cells and peritoneal macrophages, as well as by splenic B cells and macrophages. In SCID mice infected with T. cruzi, IL-10 mRNA was detected in peritoneal cells 2 days after infection. The IL-10 mRNA production was not abolished by treatment with anti-asialo GM-1 Ab before infection, which is consistent with its production by macrophages. Finally, the role of endogenous IL-10 production in the susceptibility to T. cruzi infection was demonstrated by the protection of highly susceptible C57BL/6 mice against acute disease and death from T. cruzi by the administration of neutralizing anti-IL-10 mAb. This study demonstrated an important and perhaps essential role of IL-10 in mediating in vivo susceptibility to T. cruzi infection.