Thymic generation and regeneration: a new paradigm for establishing clinical tolerance of stem cell-based therapies

Tolerance to tissue-engineering products is a major obstacle hindering the clinical application of this rapidly advancing technology. Manipulation of central tolerance, by establishing thymus chimerism of both donor and host-derived haemopoietic cells (haemopoietic stem cell transplant HSCT), should purge any T cells reactive to potential donor organ or tissue transplant. A functional thymus, however, is required to induce chimerism and repopulate the peripheral T cell pool, but age-related thymic atrophy and damage caused by ablative conditioning regimes significantly reduce thymic function and increase incident of infection-dependent morbidity and mortality. Thus rejuvenation of the thymus alongside HSCT may potentiate the use of this strategy in the clinic. In addition, the use of thymic epithelial progenitor cell technology may allow growth of ex vivo thymic tissue for use in clinical situations of immunodeficiency as well as in establishing tolerance to tissue/organ products derived from the same source.