Rebuilding the human thymus to create a tolerising system for allogeneic tissue and organ transplantation

Project Information

Rethyming

Grant agreement ID: 639429

DOI

10.3030/639429

Project closed

EC signature date 4 May 2015

Start date 1 July 2015

End date 31 December 2021

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 480 416,00

EU contribution

€ 1 480 416,00

Coordinated by

UNIVERSITY COLLEGE LONDON
United Kingdom

Periodic Reporting for period 4 - Rethyming (Rebuilding the human thymus to create a tolerising system for allogeneic tissue and organ transplantation)

Reporting period: 2020-01-01 to 2021-12-31

Summary of the context and overall objectives of the project

Organ transplantation revolutionized medicine by allowing patients to survive, often with an acceptable quality of life, thanks to organs such as kidney, heart, liver or lungs transplanted from a donor. However, the immune system of the patient would recognise the donor organ as foreign and would destroy it. To avoid this, patients are treated with drugs that inhibit the immune system and allow long-term survival of the transplanted organ. As inhibition is non-selective, the patient becomes weaker and less able to defend her/himself form infections or even tumours.
This project aims at preventing donor organ rejection by educating the immune system to recognise it as part of its own body so that no immune response is mounted on transplantation, whilst maintaining the immune response against harmful agents such as bacteria or viruses.
We are building, step-by-step, an artificial human thymus, the organ that induces maturation of the immune system and teaches it to distinguish “self” from “non-self”. We aim to define the cellular and molecular components that are able to re-educate the patient immune system to accept the donor organ as self.
If successful this project would put the basis for a rapid clinical translation in order to remove the need for immunosuppressive drugs during organ transplantation. This would have an immediate clinical benefit and impact on current and future regenerative medicine and, possibly, other immune related conditions. On the one hand patients’ quality of life would dramatically improve; on the other, costs related to treating the consequences of immune suppression would be eliminated, with a significant impact on health economy.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project has progressed so far on all the main objectives: (i) we have characterised the cellular components that can efficiently repopulate an artificial human thymus. (ii) Furthermore, we have developed a robust method to obtain thymic scaffolds that allow functional organ reconstitution and, (iii) we have tested the survival of the newly generated artificial organ upon transplantation into animal models.
An engineered thymus is potentially a life-saving treatment also for athymic patients who are affected by a life threatening condition being severly immunocompromised. We are currently exploiting this innovative technology and transferring it to a SME. This will allow further clinical development which can transform treatment of immunodeficiencies. Such a rapid translational perspectives were not foreseen at grant starting. Finally, we have identified a bona fide stem cell of the human thymus which represents an unprecedented (and unexpected) finding with important implications for understanding the biology of thymic involution and pathology beyond the regenerative medicine applications.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The project has progressed beyond the state of the art on all its novel aspects, namely the possibility to efficiently expand the cellular components of the human thymus, maintaining their potential to reconstruct a 3D organ in a dish; furthermore, we could demonstrate this structure is transplantable into animal models. The expected results until the end of the project focus on the demonstration of specific functionalities of the artificial organ which should sustain some of the key immunological functions of the human thymus. Indeed, we were able to develop a novel wholly humanised mouse model for future immunotherapeutic testing and tolerance modelling. Such a model will represent an innovative tool to test the last generatin of immunotherapeutics that currently have no basic science model and can be assessed only direclty in patients.

Human artificial thymus rebuilt ex vivo with acellular scaffold and cultured human cells