The thymus is a small but important organ; it is where thymocytes originally generated in the bone marrow mature to become T cells of the adaptive immune system. Unfortunately the active tissue of the thymus is slowly replaced by fat over the course of later life, and the supply of new T cells dwindles. This is a significant contributing cause of the age-related decline in immune function. Lacking reinforcements and replacements, the adaptive immune system becomes cluttered with senescent, exhausted, overspecialized, and just plain broken cells. It becomes overly active and inflammatory, but at the same time ineffective. It progressively becomes ever less competent when it comes to destroying cancerous and senescent cells, and defending against pathogens.

This is all well recognized, and over the years a range of efforts to regenerate the thymus have been undertaken. As of yet few have progressed much further than animal studies in mice. Recombinant KGF, which works quite well to enlarge the thymus in mice and non-human primates, failed utterly in a human trial, showing absolutely no effect. More recently, the staff at Intervene Immune have been combining some of the older and unreliable methods, such as use of growth hormone, into human tests of thymic regrowth. All of these approaches, and a few others, largely boil down to ways to upregulate FOXN1, the master controlling gene of thymic growth and T cell maturation activity. The most compelling studies in mice have been those in which FOXN1 expression was manipulated directly, and we might suspect that any therapy that grows a thymus, but fails to keep FOXN1 levels high going forward, will also fail to make a large and lasting impact on T cell generation. The thymus must be active, not just larger, and FOXN1 expression declines with age.

Tissue engineering offers an intriguing approach to the problem of the thymus, bypassing a lot of the hard work inherent in trying to manipulate expression of a given gene. (Of course replacing it with hard work of a different sort). Functional thymus tissue can be grown in small amounts, lacking a network of small-scale blood vessels, but able to be transplanted. Since thymocytes home to the thymus, thymic tissue located almost anywhere in the body will still be capable of doing its job, in principle. This has been demonstrated by implanting thymus organoids into lymph nodes, an approach being commercialized by Lygenesis. As the results here show, however, success still depends on building a suitably resilient tissue that will last for a long time following transplantation.

Gene Modification and Three-Dimensional Scaffolds as Novel Tools to Allow the Use of Postnatal Thymic Epithelial Cells for Thymus Regeneration Approaches