Researchers here demonstrate restoration of immune function in mice via transplant of tissue engineered thymus-like organoids, one of a number of lines of research that aims to restore thymic function to boost the aging immune system. A sizable part of the age-related decline of the adaptive immune system arises from a problem of supply: there are no longer enough naive T cells to mount an effective response to new threats.
Some potential approaches to solving this problem involve dealing with issues that reduce the naive T cell population, while others focus on increasing the supply of new T cells. The thymus plays a vital role in the generation of new T cells, and is very active in early life, but withers away upon reaching adulthood in a process known as thymic involution, reducing the supply of immune cells to a trickle. Thus placing new thymic tissue with youthful characteristics into old individuals should be a way to generate more T cells - a straightforward transplant works, for example:
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 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.