Modulation of Trypanosoma cruzi-specific T-cell responses after chemotherapy for chronic Chagas disease

Abstract

The aim of this review is to describe the contributions of the knowledge of T-cell responses to the understanding of the physiopathology and the responsiveness to etiological treatment during the chronic phase of Chagas disease. T-helper (Th)1 and interleukin (IL)-10 Trypanosoma cruzi-specific T-cells have been linked to the asymptomatic phase or to severe clinical forms of the disease, respectively or vice versa, depending on the T. cruzi antigen source, the patient’s location and the performed immunological assays. Parasite-specific T-cell responses are modulated after benznidazole (BZ) treatment in chronically T. cruzi-infected subjects in association with a significant decrease in T. cruzi-specific antibodies. Accumulating evidence has indicated that treatment efficacy during experimental infection with T. cruzi results from the combined action of BZ and the activation of appropriate immune responses in the host. However, strong support of this interaction in T. cruzi-infected humans remains lacking. Overall, the quality of T-cell responses might be a key factor in not only disease evolution, but also chemotherapy responsiveness. Immunological parameters are potential indicators of treatment response regardless of achievement of cure. Providing tools to monitor and provide early predictions of treatment success will allow the development of new therapeutic options.

The Significance of Discordant Serology in Chagas Disease: Enhanced T-Cell Immunity to Trypanosoma cruzi in Serodiscordant Subjects

“…A higher prevalence of IFN-γ + IL-2 + responders as well as a higher magnitude of these responses was found in SD individuals than in SP subjects. These findings are at odds with the low frequency of IL-2-producing T-cells in documented SP adult subjects (e.g., positive on all serological tests) observed herein, and in our previous studies ( 25 , 33 ).…”

Vaccine-Linked Chemotherapy Improves Benznidazole Efficacy for Acute Chagas Disease

“…Increased antigen-specific IFN-␥ significantly correlated with reduced parasitemia, and increased antigen-specific IL-4 correlated with reduced parasitemia and cardiac parasite burdens. Absence of parasitemia and parasite-specific immune responses have been used as indicators of drug efficacy in humans (19,26), and our data show that these parameters serve as informative correlates of protection in our combination treatment model as well. Limitations of this model were observed.…”

“…Studies in chronic indeterminate human patients without disease and chronic patients with disease have confirmed that antigen-specific IFN-␥ balanced by IL-10 correlates with the absence of clinical disease (25). When parasite-specific immune responses are evaluated after benznidazole treatment, antigen-specific IFN-␥ is initially increased and is believed to enhance efficacy of the drug (26,27). Further studies in preclinical models show that benznidazole cure rates are significantly reduced in mice lacking IFN-␥, IL-12, and tumor necrosis factor alpha (TNF-␣) (28).…”

WHF IASC Roadmap on Chagas Disease

“…Research to date has also hypothesized that the quality of T-cell responses and immune-regulatory mechanisms might determine the pattern of cellular responses and the severity of disease in chronic T. cruzi infection. The quality of T-cell responses might be a key factor, not only in disease evolution but also in chemotherapy responsiveness [137]. This may also explain the differing response rate to anti-parasitic treatment among children in comparison with adults, as children have a T-cell profile associated with a more robust clinical response [138].…”