Inhibition of autoimmune Chagas-like heart disease by bone marrow transplantation
Language English Country United States Media electronic-ecollection
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
PubMed
25521296
PubMed Central
PMC4270743
DOI
10.1371/journal.pntd.0003384
PII: PNTD-D-14-00432
Knihovny.cz E-resources
- MeSH
- Apoptosis MeSH
- Autoimmune Diseases prevention & control MeSH
- Chagas Cardiomyopathy prevention & control MeSH
- Chagas Disease therapy MeSH
- Immunization MeSH
- DNA, Kinetoplast genetics MeSH
- Chickens genetics MeSH
- Mutation MeSH
- Myocardium pathology MeSH
- Graft Rejection MeSH
- Bone Marrow Transplantation * MeSH
- Trypanosoma cruzi genetics immunology MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- DNA, Kinetoplast MeSH
BACKGROUND: Infection with the protozoan Trypanosoma cruzi manifests in mammals as Chagas heart disease. The treatment available for chagasic cardiomyopathy is unsatisfactory. METHODS/PRINCIPAL FINDINGS: To study the disease pathology and its inhibition, we employed a syngeneic chicken model refractory to T. cruzi in which chickens hatched from T. cruzi inoculated eggs retained parasite kDNA (1.4 kb) minicircles. Southern blotting with EcoRI genomic DNA digests revealed main 18 and 20 kb bands by hybridization with a radiolabeled minicircle sequence. Breeding these chickens generated kDNA-mutated F1, F2, and F3 progeny. A targeted-primer TAIL-PCR (tpTAIL-PCR) technique was employed to detect the kDNA integrations. Histocompatible reporter heart grafts were used to detect ongoing inflammatory cardiomyopathy in kDNA-mutated chickens. Fluorochromes were used to label bone marrow CD3+, CD28+, and CD45+ precursors of the thymus-dependent CD8α+ and CD8β+ effector cells that expressed TCRγδ, vβ1 and vβ2 receptors, which infiltrated the adult hearts and the reporter heart grafts. CONCLUSIONS/SIGNIFICANCE: Genome modifications in kDNA-mutated chickens can be associated with disruption of immune tolerance to compatible heart grafts and with rejection of the adult host's heart and reporter graft, as well as tissue destruction by effector lymphocytes. Autoimmune heart rejection was largely observed in chickens with kDNA mutations in retrotransposons and in coding genes with roles in cell structure, metabolism, growth, and differentiation. Moreover, killing the sick kDNA-mutated bone marrow cells with cytostatic and anti-folate drugs and transplanting healthy marrow cells inhibited heart rejection. We report here for the first time that healthy bone marrow cells inhibited heart pathology in kDNA+ chickens and thus prevented the genetically driven clinical manifestations of the disease.
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