Improving Pre-transplantation Thymic Epithelial Tissue Culture Using ATG

Abstract

Inborn errors of thymic stromal cell development cause impaired T-cell lymphopoiesis resulting in susceptibility to opportunistic infections and autoimmunity. Their most severe form, congenital athymia, is rare but life-threatening if left untreated. Athymia is most commonly associated with complete DiGeorge Syndrome, due to chromosome 22q11.2 microdeletions or other genetic and environmental aetiologies. This group of disorders can be corrected by transplantation of cultured donor thymus tissue, which in Europe is only available at Great Ormond Street Hospital (GOSH) in the United Kingdom. Thymus tissue is collected from immunocompetent infants in whom it is necessarily removed during cardiac surgery to treat congenital heart disease. The donated thymus tissue is then prepared for implantation into an athymic infant by culturing it for 2-3 weeks in order to deplete it of donor-derived thymocytes. While life-saving, a significant proportion of transplanted patients develop autoimmune complications. These may be due to the lack of tissue-type matching between donor and recipient, but may also result from suboptimal negative selection of autoreactive T-cells in the thymic allograft due to downregulation of the AIRE (autoimmune regulator) transcription factor during prolonged tissue culture. We thus designed a study to investigate the impact of anti-thymocyte globulin (ATG) on thymus tissue culture, both in terms of lymphodepletion and thymic stroma preservation, including AIRE expression. Preliminary findings show that addition of ATG into the culture media efficiently accelerates lymphodepletion, specifically targeting T-cell subsets. Investigations are ongoing to assess the impact of ATG on the stromal cells, but overall shortening the culture period might make it possible to improve the quality of the thymic stroma prior to implantation with likely benefits in terms of outcomes for athymic patients.