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Immunopathogenesis of experimental Chagas' disease
Chagas' disease is a serious, life-threatening disease caused by the protozoan parasite Trypanosoma cruzi in South and Central America. Neither vaccine candidate(s) nor efficient, nontoxic chemotherapeutical agents exist at the present time. Thus 20-30% of infected individuals eventually succumb to chronic Chagas' cardiomyopathy (50 000 deaths annually). Understanding the immunopathogenesis initiating and driving the disease is therefore of primary importance, and this thesis has sought to address these issues by making use of experimental animal models.
The expression of cytokines and their receptors during the initial acute phase of the disease, at which time parasites are present in blood and organs, was investigated both at mRNA processing and post-transcriptional levels. Expression of these molecules, e.g. IL-2, IL-2R and IFN-y was demonstrated to be organ-specific, indicating that T. cruzi parasites themselves can modulate the host response during infection.
In order to extrapolate experimental findings to patient scenarios, good experimental models which mimic the human disease course are required. With this in mind, a new, chronic model was developed in CBA mice. A series of studies aimed at characterizing pathology in this model revealed that it is a most appropriate experimental model for Chagas' disease. Histological analysis demonstrated extensive calcified infarctions and an extensive infiltration of immunocompetent blood cells into the myocardium of chronically-infected mice. These infiltrates comprised mainly macrophages and T cells, and an associated production of type 2 cytokines was recorded by in situ immunocytochemistry. Subsequent investigation of the expression of T cell receptors by the infiltrating T cells revealed a preferential usage of TCRBV8S2 and TCRBV8S3 elements, implicating a specific character of T cells in the genesis and/or perpetuation of the observed pathology during late-stage disease.
The extent of inflammation in the target organ the heart, already during the acute phase of the disease, prompted further study of the aorta. Prominent vasculitis was recorded in aortas of infected mice, with associated endothelial changes and an infiltration of macrophages and T cells into the adventitial layer. This observation led to investigation of whether this observed inflammation, in combination with an excess of lipids, could lead to development of atherosclerosis, a debilitating condition in which arteries become occluded due to inflammatory injury of the intima. Thus a combined regime of fat-enriched diet and T. cruzi infection was applied in CBA mice, and already after 3 months a significant development of aortic atherosclerotic lesions was observed. No such pathology was seen in mice fed only the fatty diet. Immunohistochemical analysis revealed extensive infiltration in both adventitial and intimal layers underlying the developing lesions, with associated production of IL-6 and TNF a.
These novel observations indicate that a combination of hyperlipidemia and infection-induced cardiovascular inflammation in CBA mice could provide new means for study of experimental atherosclerosis, and potentially serve to explain the changes in macro- and microvasculatures associated with chronic Chagas' disease pathology.
History
Defence date
1998-05-20Department
- Department of Microbiology, Tumor and Cell Biology
Publication year
1998Thesis type
- Doctoral thesis
ISBN-10
91-628-2990-4Language
- eng