Bioengineering Thymus Organoids to Restore Thymic Function and Induce Donor-Specific Immune Tolerance to Allografts

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 toleranc...

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Bibliographic Details
Published in:Molecular therapy 2015-07, Vol.23 (7), p.1262-1277
Main Authors: Fan, Yong, Tajima, Asako, Goh, Saik Kia, Geng, Xuehui, Gualtierotti, Giulio, Grupillo, Maria, Coppola, Antonina, Bertera, Suzanne, Rudert, William A, Banerjee, Ipsita, Bottino, Rita, Trucco, Massimo
Format: Article
Language:English
Subjects:
Allografts - immunology
Animals
Bioengineering
Epithelial Cells - cytology
Epithelial Cells - immunology
Immune Tolerance - immunology
Mice
Organoids - immunology
Original
Regenerative Medicine
Thymus Gland - cytology
Thymus Gland - growth & development
Thymus Gland - immunology
Transplantation, Homologous
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Summary: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.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2015.77