Restoration of IFN-gamma production and lymphocyte proliferation in visceral leishmaniasis.

Visceral leishmaniasis is associated with a marked depression of T cell responses, which has been characterized by the absence of IL-2 and IFN-gamma production by lymphocytes on in vitro stimulation with Leishmania Ag. The aim of this study was to evaluate both the mechanism of these immunologic abnormalities and the restoration of in vitro T cell responses to Leishmania Ags. A total of 15 untreated visceral leishmaniasis patients were evaluated. Although IFN-gamma and IL-4 levels in the supernatants of lymphocyte cultures were very low or absent, mRNA for these cytokines and for IL-10 were observed in PBMCs. Addition of IFN-gamma plus IL-2 enhanced lymphocyte proliferation by 158%. Restoration of T cell proliferative responses and IFN-gamma production was also observed by the addition of a neutralizing mAb alpha-IL-10. Neutralizing mAb alpha-IL-4 did not restore T cell responses but alpha-IL-10 and alpha-IL-4 mAbs had a synergistic effect on lymphocyte proliferation. The IFN-gamma levels in supernatants of lymphocyte cultures stimulated with Leishmania chagasi Ag or L. chagasi Ag plus alpha-IL-4, alpha-IL-10, or alpha-IL-4 plus alpha-IL-10 mAbs were 26 +/- 30 pg/ml, 41 +/- 18 pg/ml, 146 +/- 73 pg/ml, and 174 +/- 106 pg/ml, respectively. These data indicate that Th2 cell activation occurs in visceral leishmaniasis and that in vitro production of IFN-gamma and lymphocyte proliferation can be restored by blocking the inhibitory effect of the Th2 cytokines on mononuclear cells.