Changes inTrypanosoma cruzi–Specific Immune Responses after Treatment: Surrogate Markers of Treatment Efficacy

Abstract

Background As many as 20 million people are living with Trypanosoma cruzi infection in Latin American, yet few receive any treatment. The major limitation in developing and evaluating potential new drugs for their efficacy is the lack of reliable tests to assess parasite burden and elimination. Methods Adults volunteers with chronic T. cruzi infection were evaluated clinically and stratified according to the Kuschnir classification. Individuals in group 0 and group 1 clinical status were treated with 5 mg benznidazole/kg/day for 30 days. The changes in T. cruzi-specific T cell and antibody responses, as well as in clinical status, were measured periodically over the 3-5 year follow-up period and compared to pre-treatment conditions and to an untreated control group. Results The frequency of peripheral IFN- g-producing T cells specific for T. cruzi declined as early as 12 months after BZ treatment and subsequently became undetectable in a substantial proportion of treated subjects. Addtionally decreases in antibody responses to a pool of recombinant T. cruzi proteins also declined in many of these same subjects. The shift to negative IFN- g T cell responses was highly associated with an early increase in IFN- g-producing T cells with phenotypic features of effector/effector memory cells in a subset of subjects. Benznidazole treatment also resulted in an increase in naïve and early differentiated memory-like CD8+ T cells in a majority of subjects. Conclusions BZ treatment during chronic Chagas disease has a substantial impact on parasite-specific immune response that is likely to be indicative of treatment efficacy and cure.

New, Combined, and Reduced Dosing Treatment Protocols Cure Trypanosoma cruzi Infection in Mice

“…Unfortunately, inconsistent detection of T. cruzi-specific T cells [41,42] limits the translation of such assays of immunological biomarkers into use for assessing treatment outcomes in humans. Other surrogate immunological markers have shown promise in assessing treatment outcomes [43] and are likely to be more widely employed because definitive evidence of parasitological cure is impractical because of the insensitivity of even the best assays. If we are to reliably assess in humans the effectiveness of new drugs and improved treatment protocols that appear promising in mice, then we are going to need to put much more effort into developing definitive tests of cure in humans and not just clearance of detectable parasites from blood.…”

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

“…Actually, autoimmune humoral factors are, possibly, a consequence rather than a cause of the heart disease (73,91,229,332). A conclusive answer to the question of the origin of autoimmune chagasic myocardiopathy is not within reach by any canonical explanation (126,223).…”

Advances and challenges towards a vaccine against Chagas disease

“…Nonetheless, ongoing efforts for the identification of additional biomarkers are underway, including electrocardiographic, immunologic and biochemical markers, which may greatly improve and facilitate the monitoring of Chagas disease progression and thus vaccine evaluation. [86][87][88][89][90][91][92] As indicated above, a successful vaccine will need to induce a strong cellular immune response, with the activation of CD8 + cytotoxic T cells in order to effectively control T. cruzi parasites. This requirement places some constraints on the formulations and types of vaccines that may be used, since such a response is harder to induce than a humoral response.…”