Interleukin 10 production correlates with pathology in human Leishmania donovani infections.

Abstract

We have found that an important Th2 cytokine, IL-10, is produced by tissues from patients acutely infected with Leishmania donovani. In all individuals tested, IL-10 mRNA production was increased in lymph nodes taken during acute disease over that observed in postacute samples. In contrast, both preand posttreatment lymph nodes had readily detected mRNA for IFN-'y and IL-2. A down-regulating effect of IL-10 on leishmania-induced proliferative responses was demonstrated when Hu rIL-10 was added to cultures of PBMC from clinically cured individuals. PBMC from individuals with acute visceral leishmaniasis responded to stimulation with leishmania lysate by producing IL-10 mRNA. Simultaneously cultured PBMC collected from the same patients after successful chemotherapy produced no detectable IL-10 mRNA after leishmania antigen stimulation. Neutralizing anti-IL-10 mAb added to PBMC from patients with acute visceral leishmaniasis markedly increased the proliferative response to leishmania lysate. Finally, we observed mRNA for IL-10 and IFN-'y concurrently in a lesion from a patient with post-kala-azar dermal leishmaniasis (PKDL). These results indicate the production of IL-10 during L. donovani infection, and suggest a role for this cytokine in the regulation of immune responsiveness during visceral leishmaniasis. (J. Clin. Invest. 1993. 92:324-329.)

Immunoactivation and immunopathogeny during active visceral leishmaniasis

“…There is little data directly supporting this view, however, since it is difficult to obtain tissue samples from patients with the active disease. However, IFN-g mRNA expression is, as expected, present and high in bone marrow 36 , lymph node 27 , and spleen 38,50 aspirates.…”

“…It has also been found to be important in susceptibility to visceral leishmaniasis 30,49 . It has been detected in different samples of human visceral leishmaniasis: as mRNA in bone marrow 36 , lymph node 27 , and spleen 38 aspirates and at high levels in serum 1,2,15,40,50,52,63,69 ; for further information see 51 . As mentioned earlier, the possible effect of IL-10 on the production of, or proliferation of IFN-g producing cells 11,28 may not be important given the high activation of the immune response in lymphoid organs during active disease.…”

Splenic immune responses during canine visceral leishmaniasis

“…In contrast to HVL, IL-10 mRNA expression was not elevated in the spleen of L. infantum-infected dogs in this study, as was the amount of IL-10 protein in a different study [12]. Interleukin-4, a type-2 immune response cytokine, does not have a clear role in HVL [19,21]. Nevertheless, it was significantly elevated relatively early post-infection in the oligosymptomatic EI dogs studied here.…”

“…One possible explanation is that new parasites are constantly being seeded into the spleen from other highly infected tissues, where IFN-γ is not elevated. High splenic IFN-γ was also detected in people infected with L. donovani [19,21,23]. In contrast to HVL, IL-10 mRNA expression was not elevated in the spleen of L. infantum-infected dogs in this study, as was the amount of IL-10 protein in a different study [12].…”

“…Interestingly, the severity of human visceral leishmaniasis (HVL) has not been associated with increased levels of IL-4 but of IL-10, which was also detected in the spleen of infected patients [23]. Similarly, elevated levels of IFN-γ were found in biopsies taken from the spleen, lymph nodes and bone marrow of infected people [19,21,23], indicating that an unfavorable disease prognosis in humans is not related to a defect in Th1 cell response but rather to a concurrent expression of the cytokine IL-10. Interleukin-10, traditionally thought to be produced mainly by macrophages, is secreted by naturally occurring CD4+CD25+ T regulatory (Treg) cells in lesions of low dose L. major infected C57BL/6 mice.…”