Immune reconstitution after hematopoietic stem cell transplantation (HSCT), high dose chemotherapy or highly active anti-retroviral therapy (HAART) for HIV infection has emerged as a major problem, which limits the success of the therapies. When the mature T lymphocyte compartment is ablated or significantly decreased, as in the above conditions, immune reconstitution depends on production of mature T lymphocytes from immature progenitors in the thymus. Failure to regenerate a full repertoire and normal numbers of T lymphocytes results in morbidity and mortality from opportunistic infections or viral-associated malignancies. Factors contributing to defective thymopoiesis include age, intensive chemo- or radiotherapy, and graft versus host disease. Previous work by others and us has demonstrated that a major cause of post-BMT immune deficiency is the loss of thymopoietic capacity. The ability of the thymus to generate new T lymphocytes depends on two cytokines, IL-7 and c-kit ligand (KL), which are produced by thymic epithelial cells (TEC) and interact with their cognate receptors on immature thymocytes. IL-7 mediates proliferative, anti-apoptotic and differentiative effects on prothymocytes and immature thymocytes. Destruction or inhibition of the IL-7 producing TEC by irradiation or chemotherapy results in an inability to produce thymocytes normally. Recent data on aging mice also indicates that loss of intrathymic IL-7 production underlies the age-related decline in thymopoietic capacity. The general model that underlies our work is that the loss of IL-7 producing TEC underlies many forms of thymic insufficiency. We have shown that administration of either recombinant IL-7 or retrovirally transduced marrow stroma which expresses the IL-7 gene (IL-7 stroma) to mice after HSCT can restore thymopolesis, mature T lymphocyte numbers and antigen-specific immune function. The experiments in the present grant will determine whether IL-7 or IL-7 stroma can be used to enhance thymopoiesis in murine models that simulate clinical situations. Because IL-7 is a survival and proliferation factor for mature T lymphocytes, it is necessary to determine whether IL-7 treatment will exacerbate graft-versus-host disease (GVHD) after HSCT. Increasingly, transplantation is being performed with purified progenitor populations; the effects of IL-7 administration after transplantation of either purified HSC or of common lymphoid progenitors (CLP) will be determined. Previous studies have demonstrated that IL-7 treatment enhances responses to neo-antigen after HSCT; the present grant will test whether IL-7 confers protection after experimental challenge with murine cytomegalovirus infection. The durability of the thymopoietic improvements induced by IL-7 or IL-7 stroma will be examined. Together, the studies will elucidate mechanisms by which IL-7 replacement can be used to treat thymic insufficiency.
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