Up-regulation of Th1-type responses in mucosal leishmaniasis patients

Abstract

The cytokine profile produced by peripheral blood mononuclear cells (PBMC) in response to leishmania antigens and the ability of interleukin-10 (IL-10) and transforming growth factor β (TGF-β) to modulate the immune response were evaluated in 21 mucosal leishmaniasis patients. Patients with mucosal disease exhibited increased gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) secretion and decreased IL-10 secretion compared to patients with classical cutaneous leishmaniasis. CD4+ Th1 cells were the main source of IFN-γ and TNF-α production in mucosal leishmaniasis patients. Evaluation of cytokine gene expression in PBMC of these patients showed that there was strong up-regulation of IFN-γ transcripts upon stimulation with leishmania antigen, in contrast to the baseline levels of IL-10 mRNA. IL-10 suppressed IFN-γ production by 48% in cell cultures from cutaneous leishmaniasis patients and by 86% in cell cultures from healthy subjects stimulated with purified protein derivative, whereas in similar conditions IL-10 suppressed IFN-γ production by 19% in cell cultures from mucosal leishmaniasis patients stimulated with leishmania antigen. TGF-β suppressed IFN-γ levels to a greater extent in healthy subjects than in mucosal leishmaniasis and cutaneous leishmaniasis patients. These data indicate that a poorly modulated T-cell response in mucosal leishmaniasis patients leads to production of high levels of proinflammatory cytokines, such as IFN-γ and TNF-α, as well as a decreased ability of IL-10 and TGF-β to modulate this response. These abnormalities may be the basis for the pathological findings observed in this disease.