Importance of TNF-alpha in the course of acute infection with Trypanosoma cruzi: influence of its inhibition by pentoxifylline treatment

Andrade, Sônia Gumes; Magalhães, Lorena dos Anjos; Pessina, Daniel Huber

doi:10.1590/s0074-02762008005000006

Cited by 16 publications

(13 citation statements)

References 27 publications

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“…assessed the participation of TNF-α on cellular necrosis and destruction of infected macrophages in the spleen of mice during the acute phase of T. cruzi infection, they observed the expression of this cytokine in necrotic areas within the germinal center and in the red pulp, suggesting a role for TNF-α in the exacerbation of tissue damage. This same result was also observed recently by Andrade et al (2008) [33]. Furthermore, kinetic investigations on the activation of macrophages during Chagas disease, demonstrated that macrophages of mice susceptible to infection produce higher levels of TNF-α than macrophages from resistant mice strains [34] [35].…”

Section: Discussionsupporting

confidence: 88%

Different Infective Forms Trigger Distinct Immune Response in Experimental Chagas Disease

et al. 2012

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Although metacyclic and blood trypomastigotes are completely functional in relation to parasite-host interaction and/or target cell invasion, they differ in the molecules present on the surface. Thus, aspects related to the variability that the forms of T. cruzi interacts with host cells may lead to fundamental implications on the immune response against this parasite and, consequently, the clinical evolution of Chagas disease. We have shown that BT infected mice presented higher levels of parasitemia during all the acute phase of infection. Moreover, the infection with either MT or BT forms resulted in increased levels of total leukocytes, monocytes and lymphocytes, specifically later for MT and earlier for BT. The infection with BT forms presented earlier production of proinflammatory cytokine TNF-α and later of IFN-γ by both T cells subpopulations. This event was accompanied by an early cardiac inflammation with an exacerbation of this process at the end of the acute phase. On the other hand, infection with MT forms result in an early production of IFN-γ, with subsequent control in the production of this cytokine by IL-10, which provided to these animals an immunomodulatory profile in the end of the acute phase. These results are in agreement with what was found for cardiac inflammation where animals infected with MT forms showed intense cardiac inflammation later at infection, with a decrease in the same at the end of this phase. In summary, our findings emphasize the importance of taking into account the inoculums source of T. cruzi, since vectorial or transfusional routes of T. cruzi infection may trigger distinct parasite-host interactions during the acute phase that may influence relevant biological aspects of chronic Chagas disease.

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Section: Discussionsupporting

confidence: 88%

Different Infective Forms Trigger Distinct Immune Response in Experimental Chagas Disease

et al. 2012

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“…During acute T . cruzi infection, PTX administration reduced the number of TNF + cells in necrotic areas in the spleen [ 41 ]. Thus, a reduction in TNF expression was expected in our models of CCC subjected to PTX treatment.…”

Section: Discussionmentioning

confidence: 99%

Pentoxifylline Reverses Chronic Experimental Chagasic Cardiomyopathy in Association with Repositioning of Abnormal CD8+ T-Cell Response

et al. 2015

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BackgroundChronic chagasic cardiomyopathy (CCC), the main clinical sign of Chagas disease, is associated with systemic CD8+ T-cell abnormalities and CD8-enriched myocarditis occurring in an inflammatory milieu. Pentoxifylline (PTX), a phosphodiesterase inhibitor, has immunoregulatory and cardioprotective properties. Here, we tested PTX effects on CD8+ T-cell abnormalities and cardiac alterations using a model of experimental Chagas’ heart disease.Methodology/Principal FindingsC57BL/6 mice chronically infected by the Colombian Trypanosoma cruzi strain and presenting signs of CCC were treated with PTX. The downmodulation of T-cell receptors on CD8+ cells induced by T. cruzi infection was rescued by PTX therapy. Also, PTX reduced the frequency of CD8+ T-cells expressing activation and migration markers in the spleen and the activation of blood vessel endothelial cells and the intensity of inflammation in the heart tissue. Although preserved interferon-gamma production systemically and in the cardiac tissue, PTX therapy reduced the number of perforin+ cells invading this tissue. PTX did not alter parasite load, but hampered the progression of heart injury, improving connexin 43 expression and decreasing fibronectin overdeposition. Further, PTX reversed electrical abnormalities as bradycardia and prolonged PR, QTc and QRS intervals in chronically infected mice. Moreover, PTX therapy improved heart remodeling since reduced left ventricular (LV) hypertrophy and restored the decreased LV ejection fraction.Conclusions/SignificancePTX therapy ameliorates critical aspects of CCC and repositioned CD8+ T-cell response towards homeostasis, reinforcing that immunological abnormalities are crucially linked, as cause or effect, to CCC. Therefore, PTX emerges as a candidate to treat the non-beneficial immune deregulation associated with chronic Chagas' heart disease and to improve prognosis.

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“…Recently, TNF-α blockade has been shown to decrease necrotic areas in the spleen during acute T. cruzi infection (Andrade et al 2008). Conversely, treatment with Etanercept (soluble human TNFR2/p75 that binds TNF-α and lymphotoxin α) aggravated chronic chagasic cardiomyopathy in hamsters, leading to the claim that the absence of TNF-α signaling may be deleterious to the failing heart in Chagas disease cardiomyopathy (Bilate et al 2007).…”

Section: Discussionmentioning

confidence: 99%

TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-α blockade

Kroll-Palhares

Silvério

Silva

et al. 2008

Mem. Inst. Oswaldo Cruz

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Importance of TNF-alpha in the course of acute infection with Trypanosoma cruzi: influence of its inhibition by pentoxifylline treatment

Abstract: Infection of C3H/He mice with the Peruvian strain of

Cited by 16 publications

References 27 publications

Different Infective Forms Trigger Distinct Immune Response in Experimental Chagas Disease

Different Infective Forms Trigger Distinct Immune Response in Experimental Chagas Disease

Pentoxifylline Reverses Chronic Experimental Chagasic Cardiomyopathy in Association with Repositioning of Abnormal CD8+ T-Cell Response

TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-α blockade

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