Inhibition of Autoimmune Chagas-Like Heart Disease by Bone Marrow Transplantation

0442372 - ÚMG 2015 RIV US eng J - Článek v odborném periodiku
Guimaro, M.C. - Alves, R. J. V. - Rose, E. - Sousa, A.O. - Rosa, A.D. - Hecht, M.M. - Sousa, M.V. - Andrade, R.R. - Vital, T. - Plachý, Jiří - Nitz, N. - Hejnar, Jiří - Gomes, C.C. - Teixeira, A.R.L.
Inhibition of Autoimmune Chagas-Like Heart Disease by Bone Marrow Transplantation.
PLoS Neglected Tropical Diseases. Roč. 8, č. 12 (2014). ISSN 1935-2735. E-ISSN 1935-2735
Institucionální podpora: RVO:68378050
Klíčová slova: Chagas disease * inbred chicken * adoptive transfer of immunity
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 4.446, rok: 2014

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 CD8 alpha(+) and CD8 beta(+) effector cells that expressed TCR gamma delta, v beta 1 and v beta 2 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.
Trvalý link: http://hdl.handle.net/11104/0245202