Medical researchesr from UC San Francisco have used embryonic stem cells to construct a functioning mouse thymus in the laboratory. When implanted into a living mouse, this laboratory-made thymus can successfully foster the development of T cells, which the body needs to fight infections and prevent autoimmune reactions.
This achievement marks a significant step toward developing new treatments for autoimmune disorders such as type 1 diabetes and other autoimmune diseases, such as systemic lupus erythematosis and ulcerative colitis.
This research team was led by immunologist Mark Anderson and stem cell researcher Matthias Hebrok. They used a unique combination of growth factors to push the embryonic stem cells into a particular developmental trajectory. After a period of trial and error, they eventually found a formula that produced functional thymus tissue.
In our bodies, the thymus lies just over the top of our heart, and it serves to instruct T lymphocytes (a type of white blood cell) what to attack and what to leave alone. Because T cells serve a vital role in the immune response, the thymus serves a vital function.
Typically, each T cell attacks a foreign substance that it identifies by binding the foreign substance to its cell surface receptor. This T cell-specific receptor is made in each T cell by a set of genes that are randomly shuffled, and therefore, each T cell has a unique cell receptor that can bind particular foreign molecules. Thus each T cell recognizes and attacks a different foreign substance.
With in the thymus, T cells that attack the body’s own proteins are eliminated. Thymic cells express major proteins from elsewhere in the body. The T cells that enter the thymus first undergo “Positive Selection” in which the T cell comes in contact with self-expressed proteins that are found in almost every cell of the body and are used to tell “you” from something that is not from “you.” In order to destroy cells that do not bear these self-expressed proteins, they must be able to properly identify them. If T cells that enter the thymus cannot properly recognize those self-expressed proteins (known as MHC or major histocompatibility complex proteins for those who are interested), the thymus destroys them. Second, T cells undergo “Negative Selection” in which if the T cell receptor binds to self MHC proteins, that T cell is destroyed to avoid autoimmunity.
The thymus tissue grown in the laboratory in this experiment was able to nurture the growth and development of T cells. It could act as a model system to study patients with fatal diseases from which there are no effective treatments, according the Mark Anderson.
As an example, DiGeorge Syndrome is caused by a small deletion of a small portion of chromosome 22 and infants born with DiGeorge Syndrome are born without a thymus and they usually die during infancy.
Other applications include manipulating the immune system to accept transplanted tissues such as implanted stem cells or organs from donors that are not a match to the recipient.
Anderson said, “The thymus is an environment in which T cells mature and where they also are instructed on the difference between self and nonself.” Some T cells are prepared by the thymus to attack foreign invaders and that includes transplanted tissue. Other T cells that would potentially attack our own tissues are eliminated by the thymus.
Laboratory-induced thymus tissue could be used to retrain the immune system in autoimmune diseases so that the T cells responsible for the autoimmune response eventually ignore the native tissues they are attacking.
Hebrok warns that he and his team have not perfectly replicated a thymus. Only about 15% of the cells are successfully directed to become thymus tissue with the protocols used in this study. Nevertheless, Anderson asserted, “We now have developed a tool that allows us to modulate the immune system in a manner that we never had before.”