Although the problem of immune reconstitution after HSCT has been addressed indirectly by supportive care measures, new knowledge of the biology of transplantation should allow us to move forward in directly attacking the problem. Strategies to improve the development of T lymphocytes via thymic-dependent pathways involve the generation, isolation, and manipulation of prethymic cells, including CLPs. Understanding of the reciprocal relationships between lymphoid progenitors and the thymic microenvironment have allowed small-animal model testing of either IL-7 replacement or FGF-mediated protection and regeneration of TECs. The elucidation of the TCR and cytokine requirements for the thymus-independent homeostatic cycling and peripheral expansion of mature T cells is leading to studies of either enhancement of immune responses to antigens or to improved survival and efficacy of adoptively transferred T lymphocytes. Although all of these approaches have solid preclinical supporting data, a major challenge to the HSCT community will be the implementation of clinical trials that will allow proper evaluation of their safety, efficacy, and best use.
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