title: Attenuation of transplant arteriosclerosis by oral feeding of major histocompatibility complex encoding chitosan-DNA nanoparticles.
abstract: One promising approach for the induction of transplant tolerance is the pre-treatment of transplant recipients with donor MHC-alloantigen. Our study focuses on the oral delivery of MHC-antigen encoding genes via chitosan-DNA nanoparticles to modulate the alloimmune response in order to reduce the development of transplant arteriosclerosis, the hallmark feature of chronic rejection after heart transplantation. Therefore, we performed fully allogeneic mouse abdominal aortic transplants using C57BL/6 (H2(b)) mice as donors and CBA.J (H2(k)) mice as recipients. Aortic grafts were analyzed by histology and morphometry on day 30 after transplantation, levels of circulating alloantibodies were detected by FACS analysis. Pre-treatment of recipient mice with chitosan-DNA nanoparticles encoding for K(b), one of the MHC-I molecules of the donor, resulted in a significant reduction of intimal proliferation compared to untreated controls. When Ovalbumin was fed instead of K(b) encoding nanoparticles (K(b)-NP) or Balb/c (H2(d)) grafts were used instead of C57BL/6 (H2(b)) grafts as antigen controls, both groups showed no reduction of intimal thickness indicating an antigen-specific mechanism. In addition, analysis of peripheral blood of the transplanted mice showed significant suppression of alloantibody formation in the K(b)-NP fed group compared to all other allogeneic transplanted groups suggesting modulation of the humoral immune response. These results demonstrate the potential of chitosan-DNA nanoparticles to induce K(b)-specific tolerance and to reduce the development of transplant arteriosclerosis.
authors.affiliation: Department of Internal Medicine 5, Hematology/Oncology and Institute for Clinical Immunology, Friedrich-Alexander University Erlangen-Nürnberg, Glückstrasse 4A, 91054 Erlangen, Germany. katja.goldmann@uk-erlangen.de
authors.forename: Katja
authors.initials: K
authors.lastname: Goldmann
authors.forename: Julia
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Eckl
authors.forename: Bernd M
authors.initials: BM
authors.lastname: Spriewald
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Ensminger
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001162:Arteriosclerosis Obliterans / Q000209:etiology / Q000517:prevention & control; D001572:Benzofurans; D048271:Chitosan / Q000008:administration & dosage* / Q000378:metabolism; D002908:Chronic Disease; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D016027:Heart Transplantation; D007519:Isoantigens / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D053758:Nanoparticles / Q000008:administration & dosage*; D011183:Postoperative Complications / Q000517:prevention & control*; D011804:Quinolines; D023001:Transplantation Tolerance; D016896:Treatment Outcome
chemical_list: C576715:(3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; D001572:Benzofurans; D007519:Isoantigens; D011804:Quinolines; D004247:DNA; D048271:Chitosan