Sequential combined treatment with allopurinol and benznidazole in the chronic phase of Trypanosoma cruzi infection: a pilot study

Pérez‐Mazliah, Damián; Alvarez, M; Cooley, Gretchen; Lococo, Bruno; Bertocchi, Graciela; Petti, Marcos; Albareda, María Cecilia; Armenti, Alejandro; Tarleton, Rick L.; Laucella, Susana A.; Viotti, Rodolfo

doi:10.1093/jac/dks390

Cited by 47 publications

(49 citation statements)

References 61 publications

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“…It has been shown that CD127 - CD132 + T cells are mainly comprised by short-live effector T cells (25), concurring with the high frequencies of total effector CD4 and CD8 T cells found in chronically T. cruzi -infected subjects (3,4). Despite that patients in the chronic phase of the infection, including those with more severe forms of the disease, display an activated immune status (3,4, 26-29), herein we show that the capability to modulate IL7R receptor components are impaired in more severe clinical stages. Our experiments of coculture of PBMC with T. cruzi trypomastigotes, support that T. cruzi can mediate the modulation of the IL-7R components.…”

Section: Discussioncontrasting

confidence: 60%

Perturbed T Cell IL-7 Receptor Signaling in Chronic Chagas Disease

Albareda

Pérez‐Mazliah

Natale

et al. 2015

The Journal of Immunology

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We have previously demonstrated that immune responses in subjects with chronic Trypanosoma cruzi infection display features common to other persistent infections with signs of T cell exhaustion. Alterations in cytokine receptor signal transduction have emerged as one of the cell-intrinsic mechanisms of T cell exhaustion. Herein, we performed an analysis of the expression of IL-7R components (CD127 and CD132) on CD4+ and CD8+ T cells, and evaluated IL-7-dependent signaling events in patients at different clinical stages of chronic chagasic heart disease. Subjects with no signs of cardiac disease showed a decrease in CD127+CD132+ cells and a reciprocal gain of CD127-CD132+ in CD8+ and CD4+ T cells compared to either patients exhibiting heart enlargement or uninfected controls. T. cruzi infection, in vitro, was able to stimulate the downregulation of CD127 and the upregulation of CD132 on T cells. IL-7-induced phosphorylation of STAT5 as well as Bcl-2 and CD25 expression were lower in T. cruzi-infected subjects compared with uninfected controls. The serum levels of IL-7 was also increased in chronic chagasic patients. The present study highlights perturbed IL-7/IL-7R T cell signaling through STAT5 as a potential mechanism of T cell exhaustion in chronic T. cruzi infection.

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Section: Discussioncontrasting

confidence: 60%

Perturbed T Cell IL-7 Receptor Signaling in Chronic Chagas Disease

Albareda

Pérez‐Mazliah

Natale

et al. 2015

The Journal of Immunology

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“…CD4 + and CD8 + T cells 38 and decreased the percentage of total effector CD4 + T cells to values similar to those of uninfected subjects after 24 months. 39 So, the expression of CCR7 seems to be inversely correlated to severity of disease.…”

Section: F I G U R E 7 Severity Of Chronic Chagasic Cardiomyopathy Comentioning

confidence: 57%

“…Indeed, we showed negative correlation between reduced percentage of naive CD4 + and CD8 + T cells and severity of cardiac Chagas disease and between naïve CD4 + T cells and the diameter of the LV. In this way, antiparasitic therapy in patients with Chagas disease restored the levels of total naive (CD45RA + CCR7 + CD62L + ) CD4 + and CD8 + T cells and decreased the percentage of total effector CD4 + T cells to values similar to those of uninfected subjects after 24 months . So, the expression of CCR7 seems to be inversely correlated to severity of disease.…”

Section: Discussionmentioning

confidence: 82%

Increased frequencies of circulating CCR5+ memory T cells are correlated to chronic chagasic cardiomyopathy progression

Roffê

Santos

et al. 2019

Journal of Leukocyte Biology

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The infection with the protozoan parasite Trypanosoma cruzi causes Chagas disease, a neglected tropical disease in Latin America and an imported emerging disease worldwide. Chronic Chagasic cardiomyopathy (CCC), a progressive inflammatory and fibrosing disease, is the most prominent clinical form of Chagas disease, culminating in heart failure and high rates of sudden death. CCC pathogenesis is influenced by both host and parasite factors and is proposed to be mostly immune‐driven. Chemokines are crucial players in orchestrating immune cell recruitment to infected tissues and inflammation. Herein, we investigated inflammatory chemokine receptor expression on circulating T cells in patients stratified by CCC severity. Compared to asymptomatic individuals, we found increased percentages of effector CD4+ T cells and central memory CD4+ and CD8+ T cells expressing CCR5 in patients with structural cardiopathy, but normal global ventricular function and no symptoms of chronic heart failure. Even naïve T cells expressed CCR5 in these patients. In contrast, reduced frequencies of CD4+ and CD8+ effector T cells expressing CXCR3 were observed in patients presenting with severe heart disease. Patients with increased left ventricular diameter, heart enlargement, and insufficiency had higher frequencies of CCR5+ effector and effector memory CD8+ T cells. Moreover, the percentage of effector CCR5+ CD8+ T cells was increased in patients with a reduced ejection fraction. Our results show that high expression CCR5 and low expression of CXCR3 on circulating T cells are associated with worse prognosis, possibly reflecting immune‐mediated cardiac remodeling of CCC.

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“…In addition, the scarcity of knowledge about the pharmacology of benznidazole has led the scientific community to point out the necessity to test old and new schemes to improve efficiency and achieve a reduction in adverse effects. Several options have been proposed, including a reduction in dose, changes in the scheme of treatment, or combination of antiparasitic drugs (23).…”

Section: Discussionmentioning

confidence: 99%

New Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected with Trypanosoma cruzi: a Pilot Short-Term Follow-Up Study with Adult Patients

Alvarez¹,

Hernández

Bertocchi³

et al. 2016

Antimicrob Agents Chemother

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There is a clinical need to test new schemes of benznidazole administration that are expected to be at least as effective as the current therapeutic scheme but safer. This study assessed a new scheme of benznidazole administration in chronic Chagas disease patients. A pilot study with intermittent doses of benznidazole at 5 mg/kg/day in two daily doses every 5 days for a total of 60 days was designed. The main criterion of response was the comparison of quantitative PCR (qPCR) findings prior to and 1 week after the end of treatment. The safety profile was assessed by the rate of suspensions and severity of adverse effects. Twenty patients were analyzed for safety, while qPCR was tested for 17 of them. The average age was 43 ؎ 7.9 years; 55% were female. Sixty-five percent of treated subjects showed detectable qPCR results prior to treatment of 1.45 (0.63 to 2.81) and 2.1 (1.18 to 2.78) parasitic equivalents per milliliter of blood (par.eq/ml) for kinetoplastic DNA (kDNA) qPCR and nuclear repetitive sequence satellite DNA (SatDNA) qPCR, respectively. One patient showed detectable PCR at the end of treatment (1/17), corresponding to 6% treatment failure, compared with 11/17 (65%) patients pretreatment (P ‫؍‬ 0.01). Adverse effects were present in 10/20 (50%) patients, but in only one case was treatment suspended. Eight patients showed mild adverse effects, whereas moderate reactions with increased liver enzymes were observed in two patients. The main accomplishment of this pilot study is the promising low rate of treatment suspension. Intermittent administration of benznidazole emerges a new potential therapeutic scheme, the efficacy of which should be confirmed by long-term assessment posttreatment.

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Sequential combined treatment with allopurinol and benznidazole in the chronic phase of Trypanosoma cruzi infection: a pilot study

Cited by 47 publications

References 61 publications

Perturbed T Cell IL-7 Receptor Signaling in Chronic Chagas Disease

Perturbed T Cell IL-7 Receptor Signaling in Chronic Chagas Disease

Increased frequencies of circulating CCR5+ memory T cells are correlated to chronic chagasic cardiomyopathy progression

New Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected with Trypanosoma cruzi: a Pilot Short-Term Follow-Up Study with Adult Patients

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