| Allogeneic hematopoietic stem cell transplantation (allo-SCT) is an established treatment modality for patients with a variety of hematological disorders. Impaired immune reconstitution represents one of the major obstacles associated with allo-SCT, especially using grafts from unrelated or cord blood donors. The reconstitution of lymphocytes is characterized by a slow recovery of newly developed T cells (thymopoiesis). This also holds for naturally occurring CD4+Foxp3+ regulatory T cells (Treg). So, the recovery of both T cell-mediated immunity and immunological tolerance after allo-SCT is retarded, especially after alternative donor SCT. In contrast to pediatric patients, adult recipients of allogeneic stem cell grafts show a very retarded recapitulation of thymopoiesis. Apart from the age related involution of the thymus, direct damaging effects of graft versus host disease and chemo/radiotherapy to the thymic epithelium may result in an absent or severely compromised thymic function. It appeared that defective thymopoiesis is central to the observed impaired immune reconstitution after alternative donor SCT. Our research focusses on: 1) the improvement of functional T cell mediated immunity and immunological tolerance after allo-SCT using cytokine intervention therapy (Braakman) 2) the development of new approaches to improve thymic function by use of specific cytokines and the development of thymic regenerative cellular therapy using embryonic stem cells (Cornelissen) 3) the regulation of human lymph node development (Cupedo). These studies are performed in various murine stem cell transplantation models, in humanized mice and with primary human tissues. |
