title: Inhibition of autoimmune Chagas-like heart disease by bone marrow transplantation.
abstract: BACKGROUND
  Infection with the protozoan Trypanosoma cruzi manifests in mammals as Chagas heart disease. The treatment available for chagasic cardiomyopathy is unsatisfactory.
  
  
  RESULTS
  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
  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.
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Guimaro
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Rozeneide M
authors.initials: RM
authors.lastname: Alves
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Ester
authors.initials: E
authors.lastname: Rose
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Alessandro O
authors.initials: AO
authors.lastname: Sousa
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Ana
authors.initials: A
authors.lastname: de Cássia Rosa
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Mariana M
authors.initials: MM
authors.lastname: Hecht
authors.affiliation: Laboratory of Protein Chemistry, Institute of Biology, University of Brasilia, Federal District, Brazil.
authors.forename: Marcelo V
authors.initials: MV
authors.lastname: Sousa
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Rafael R
authors.initials: RR
authors.lastname: Andrade
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Tamires
authors.initials: T
authors.lastname: Vital
authors.affiliation: Laboratory of Viral and Cellular Genetics, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Plachy
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Nadjar
authors.initials: N
authors.lastname: Nitz
authors.affiliation: Laboratory of Viral and Cellular Genetics, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Hejnar
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Clever C
authors.initials: CC
authors.lastname: Gomes
authors.affiliation: Chagas Disease Multidisciplinary Research Laboratory, Center for Research and Prevention of Neglected Diseases, Faculty of Medicine, University of Brasilia, Federal District, Brazil.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: L Teixeira
mesh_terms: D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D002598:Chagas Cardiomyopathy / Q000517:prevention & control*; D014355:Chagas Disease / Q000628:therapy*; D002645:Chickens / Q000235:genetics; D018105:DNA, Kinetoplast / Q000235:genetics; D006084:Graft Rejection; D007114:Immunization; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D014349:Trypanosoma cruzi / Q000235:genetics / Q000276:immunology
chemical_list: D018105:DNA, Kinetoplast