Presence of Circulating Levels of Interferon-<FONT FACE=Symbol>g</font>, Interleukin-10 and Tumor Necrosis Factor-<FONT FACE=Symbol>a</font> in Patients with Visceral Leishmaniasis

Abstract

Experimental murine L. major infection is characterized by the expansion of distinct CD4+ T cell subsets. The Th1 response is related to production of IFN-gamma and resolution of infection, whereas Th-2 response with production of IL-4 and IL-10 and dissemination of infection. The objective of this study was to measure the circulating levels of IFN-gamma, IL-10 and TNF-alpha in patients with visceral leishmaniasis (VL) before, during and at the end of therapy and to examine the association between cytokine levels and activity of VL. Fifteen patients with VL were evaluated. The cytokine determinations were done by using the enzyme-linked immunoassay (ELISA) before, during and at the end of therapy. At baseline, we detected circulating levels of IFN-gamma in 13 of 15 patients (median = 60 pg/ml); IL-10 in 14 of 15 patients (median = 141.4 pg/ml); and TNF-alpha in 13 of 14 patients (median = 38.9 pg/ml). As patients improved, following antimonial therapy, circulating levels of IL-10 showed an exponential decay (y = 82.34 e-0, 10367x, r = -0.659; p < 0.001). IFN-gamma was no longer detected after 7/14 days of therapy. On the other hand, circulating levels of TNF-alpha had a less pronounced decay with time on therapy, remaining detectable in most patients during the first seven days of therapy (y = 36.99-0.933x, r = -0.31; p = 0.05). Part of the expression of a successful response to therapy may, therefore, include reduction in secretion of inflammatory as well as suppressive cytokines. Since IL-10 and IFN-gamma are both detected prior to therapy, the recognized cellular immune depression seen in these patients may be due to biological predominance of IL-10 (type 2 cytokine), rather than lack of IFN-gamma (type 1 cytokine) production.

Interleukin-10 (IL-10) in Experimental Visceral Leishmaniasis and IL-10 Receptor Blockade as Immunotherapy

“…The BALB/c mice used in our anti-IL-10R treatment experiments fulfilled this requirement (29,33,38); studies in human visceral infection also indicate simultaneous expression of a Th1 cell cytokine response, albeit reduced or deactivated (15,19,22,23,33,56). IL-10R blockade also appears to represent a viable alternative to administering activating Th1 cytokines in exogenous form (33,38), the prior strategy employed to induce immunoenhancement in this L. donovani model.…”

“…Since IL-10 has been implicated as an immunodeactivating factor in human visceral leishmaniasis (5,11,15,18,19,22,55,56), inhibiting its action represents a logical therapeutic approach. Our results, in animals modified to express both ends of the spectrum of IL-10's effects, firmly identify the cytokine as appropriate to inhibit and provide a rationale for targeting This effect, demonstrated in our normal BALB/c mice treated therapeutically with anti-IL-10R monoclonal antibody, has also been well illustrated in C57BL/6 mice chronically infected with L. major (7).…”

Immunoactivation and immunopathogeny during active visceral leishmaniasis

“…Two studies, for example, examined IFN-g levels in both the supernatant of Leishmania antigen-induced PBMCs and the serum; low levels were found in the first sample, while high levels were found in the second sample 9,15 . TNF-a, another cytokine important for protection, was also found at elevated levels in the serum 20,70 .…”

“…Because it plays an important role in susceptibility to Leishmania major-induced cutaneous leishmaniasis 56 , levels of IL-4 have been examined in cases of human visceral leishmaniasis. The level of IL-4 in serum varies, and IL-4 was detected in some patients 20,50,63,69 but not in others 2,15,52 . IL-4 mRNA expression was detected in bone marrow in approximately half of the cases 38 .…”

Clinical and Experimental Advances in Treatment of Visceral Leishmaniasis

“…The failure to spontaneously control visceral infection may reflect an intrinsically inert or unstable Th1-cell-inducing mechanism (87); however, most information points instead to active suppression. Factors implicated experimentally and/or clinically in deactivating Th1-cell responses and favoring visceral infection include Th2-cell-associated cytokines (IL-4, IL-10, IL-13) (11,12,18,34,51,56,61,68,80,81,86,88,100,120,150,168,193) and transforming growth factor-␤ (TGF-␤) (71,148,187,188). Nevertheless, if the Th1-cell response evolves and predominates, the parallel generation of regulatory cytokines recognized as suppressive appears of little consequence (102) and probably beneficially limits tissue inflammation.…”