Zanieri, Luca; (2024) Reconstructing an artificial human thymus ex vivo and in vivo. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The thymus is a primary lymphoid organ involved in the development of T cell which have to undergo differentiation and repertoire selection. The thymic stroma is characterised by a highly complex micro-environment, composed of diverse cell types. Specifically, thymic epithelial cells (TECs), interstitial cells (TIC) and dendritic cells (DCs) control T cell maturation by driving thymocytes through positive and negative selection. Newly developed T cells acquire the capacity to recognise self from non-self antigens (Central Tolerance) and the ability to fight against diverse pathogens. DiGeorge Syndrome (DGS) is a congenital disease characterised by the absence of the thymus and therefore DGS patients have impaired T cell maturation. To date the only clinically approved treatment is the transplantation of post-natal thymus slices from a healthy donor into DGS quadriceps muscle. However, thymic transplantation does not restore normal levels of T cells as in a healthy child and the carryover of donor’s thymocytes represents a potential risk for Graft versus Host Disease (GvHD). This therapy was developed as a life-saving treatment and an experimental model to test both functionality and toxicity of transplanted thymus slices is missing. My project aims at developing a proof of principle of an alternative therapy for DGS patients. To this purpose, I reconstituted a human engineered thymus by isolating each human thymic component i.e., TEC, TIC and Extra Cellular Matrix (ECM), and re-assembling and culturing them ex vivo. The engineered thymus could also be implanted and therefore it may represent an alternative translational approach for athymic patients as it will offer a robust and reproducible source of thymic stroma and overcome the problem of T cell contaminants from donor organs. In addition, I investigated how thymic stroma survive within the thymus slices currently used for transplantation in DGS patients both upon in vitro cultivation and transplantation into athymic immunodeficient mice. Finally, this tissue engineering approach will offer a currently missing model for studying human thymopoiesis both in vitro and upon transplantation into humanised athymic mice, which could be compared with the implanted thymus slices. In this study, I report the proof of principle that human T cell development can be recapitulated ex vivo.

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