3-Hydroxy Kynurenine (3-HK) treatment for T. cruzi infection ameliorates the symptoms of Chronic Chagas’ heart disease controlling the parasite replication and the inflammatory associated pathology

KNUBEL, C; MARTINEZ, FERNANDO; RIVAROLA, WALTER; MOTRAN, CLAUDIA CRISTINA

Buenos Aires

Congreso; First French-Argentine Immunology Congress. LVIII Reunion Anual de la Sociedad Argentina de Inmunologia.; 2010

Sociedad Argentina de Inmunologia

Chronic Chagas’ heart disease, caused by the parasite T. cruzi, is an inflammatory cardiomyopathy that may lead to cardiac dilatation, congestive heart failure, and death. We demonstrated that the therapeutic administration of 3-HK, a catabolite of the tryptophan degradation driven by Indoleamine 2,3 dioxygenase (IDO), decrease the parasitemia of T. cruzi infected mice and improve their survival. To investigate the effect of 3-HK treatment on the outcome of chronic Chagas’ heart disease, BALB/c mice were infected with 500 tripomastigotes of T. cruzi and 5 days post infection (dpi), the mice were i.p. treated with 1 mg/kg/d of 3-HK (3-HK mice) or PBS (control mice) for 5 days (dpi5-10).  Electrocardiograms performed at 60 dpi revealed that 3-HK mice showed a significant decrease in the incidence and the severity of the alterations compared with controls (p<0.02).  Next, we investigated whether 3-HK treatment could condition the development of a particular immune response able to contribute to the control of the infection or the inflammatory associated pathology. Spleen cells (SMC) from 16 dpi (acute) or 63 dpi (chronic) mice that were treated or not with 3-HK were cultured with an extract of T. cruzi (F105) and the secreted cytokines determined by ELISA.  SMC from acutely infected 3-HK mice secreted lower INF-g and IL-5 levels (p<0.02) and more than 4-times the TGF-b levels (p<0.001) than those secreted by control mice. During the chronic phase of the infection, SMC from 3-HK mice showed a long term Th1-like response able to secrete the protective cytokine IFN-g (p<0.02) but not the pathogenic cytokine TNF while SMC from control mice did not show significant cytokine response against F105 compared with non infected mice.  In addition, 3-HK mice presented an important increased in CD4+CD25+Foxp3+, GITR+ and IL-10+ Treg populations.  Our results show evidence for 3-HK as a novel therapeutic treatment to control both the parasite replication and the inflammatory associated pathology