title: Bioengineering Thymus Organoids to Restore Thymic Function and Induce Donor-Specific Immune Tolerance to Allografts.
abstract: One of the major obstacles in organ transplantation is to establish immune tolerance of allografts. Although immunosuppressive drugs can prevent graft rejection to a certain degree, their efficacies are limited, transient, and associated with severe side effects. Induction of thymic central tolerance to allografts remains challenging, largely because of the difficulty of maintaining donor thymic epithelial cells in vitro to allow successful bioengineering. Here, the authors show that three-dimensional scaffolds generated from decellularized mouse thymus can support thymic epithelial cell survival in culture and maintain their unique molecular properties. When transplanted into athymic nude mice, the bioengineered thymus organoids effectively promoted homing of lymphocyte progenitors and supported thymopoiesis. Nude mice transplanted with thymus organoids promptly rejected skin allografts and were able to mount antigen-specific humoral responses against ovalbumin on immunization. Notably, tolerance to skin allografts was achieved by transplanting thymus organoids constructed with either thymic epithelial cells coexpressing both syngeneic and allogenic major histocompatibility complexes, or mixtures of donor and recipient thymic epithelial cells. Our results demonstrate the technical feasibility of restoring thymic function with bioengineered thymus organoids and highlight the clinical implications of this thymus reconstruction technique in organ transplantation and regenerative medicine.
authors.affiliation: Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
authors.forename: Asako
authors.initials: A
authors.lastname: Tajima
authors.affiliation: Department of Chemical and Petroleum Engineering, University of Pittsburgh School of Engineering, Pittsburgh, Pennsylvania, USA.
authors.forename: Saik Kia
authors.initials: SK
authors.lastname: Goh
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Xuehui
authors.initials: X
authors.lastname: Geng
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Gualtierotti
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Grupillo
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Current address: Section of Endocrinology, Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), University of Palermo, Palermo, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Coppola
authors.affiliation: Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Bertera
authors.affiliation: Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Rudert
authors.affiliation: Department of Chemical and Petroleum Engineering, University of Pittsburgh School of Engineering, Pittsburgh, Pennsylvania, USA.
authors.forename: Ipsita
authors.initials: I
authors.lastname: Banerjee
authors.affiliation: Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Bottino
authors.affiliation: Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, Pennsylvania, USA. Electronic address: mtrucco1@wpahs.org.
authors.forename: Massimo
authors.initials: M
authors.lastname: Trucco
mesh_terms: D064591:Allografts / Q000276:immunology; D000818:Animals; D057005:Bioengineering; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D009940:Organoids / Q000276:immunology; D044968:Regenerative Medicine; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development* / Q000276:immunology; D014184:Transplantation, Homologous