The thymus in allogeneic haematopoietic stem cell transplantation

After hematopoietic stem cell transplantation (HSCT), a severe deficiency of the adaptive immunity is observed and lasts up to 12 to 24 months. Reconstitution of the T-cell compartment is a slow process which involves 2 major pathways. The thymus-independent pathway is the main contributor of T cell reconstitution in the 6 to 12 months post-HSCT. It involves mature donor T lymphocytes present in the graft. These cells protect the host from infections and from relapse of haematological malignancies (Graft Versus Tumour activity). However, these cells the support of alloreactivity. They may generate graft versus host disease (GVHD) and thymus epithelial cell (TEC) alterations. This pathway also involves residual recipient T lymphocytes that can be responsible for graft rejection. The second pathway results in the do novo production of naive T cells generated from donor bone marrow progenitors. These progenitors migrate into the thymus where they expand and differentiate into mature T cells with a diversified TCR repertoire. In addition, the newly generated T cells are tolerant to both donor and host antigens. However, they are usually detected only after the 3rd month post-allograft and this process is particularly slow in patients over 30 years-old and in GVHD. Structural and functional alterations of the thymus gland, mostly induced by the conditioning regimen and the donor T cells, contribute to the slow immune reconstitution and to the generation of an aberrant TCR repertoire with frequent autoimmune disorders. Therefore, new approaches are required to stimulate and optimize the thymo-dependent pathway. These should include strategies aiming to preserve or restore the thymus gland architecture, in particular the TEC integrity, organization and functions. They must also include approaches that can boost thymopoiesis together with manipulation of post-thymic T cell development and function.