Post-BMT immune deficiency causes significant morbidity and mortality in BMT recipients. Most recipients of T-cell replete matched sibling or unrelated donor HSC grafts experience late post-BMT infections, Strategies are urgently needed to speed thymopoietic recovery. A major cause of post-BMT immune deficiency is the loss of thymopoietic capacity. Normal thymopoiesis depends on the interaction of the thymic stroma-derived receptors and ligands. Damage to thymic epithelial cells (TEC) by pre-BMT conditioning impairs the ability of the thymus to generate mature T lymphocytes after BMT. Our overall hypothesis is that thymic microenvironmental injury is the major limiting factor responsible for slow T cell immune reconstitution and function, as indicated by the predisposition of the recipient to experience late infections post-BMT. Specific cytokines have been shown to regulate the development and proliferation of epithelial cells, key components in the thymic microenvironment which are needed for effective thymopoiesis. Keratinocyte growth factor (KGF) is one such cytokine. Based on the model that TEC are targets for BMT-associated thymic damage, we hypothesized that KGF pre-treatment would prevent TEC damage after BMT. Our preliminary data indicate this to be the case. In this proposal, we will explore the mechanism(s) responsible for the effects of KGF on facilitating thymopoiesis in BMT recipients. Inhibition of p53 has been shown to protect mice from the lethal genotoxic stress induced by conditioning regimen injury. Our preliminary data indicate a p53 inhibitor speeds thymopoietic recovery in lethally irradiated recipients of allogeneic TCD BM. We will determine whether KGF and p53 inhibitors operate on non-overlapping pathways and thus may be additive or synergistic in protecting TEC against injury. Thymopoiesis is well-known to decline with age, beginning after puberty. The thymic microenvironment is severely disrupted in aging and that blocking sex steroid production normalizes thymopoiesis. We propose to determine whether pre-BMT chemical blockade of sex steroid production using LHRH analogues (agonist or antagonist) will speed thymopoietic recovery in young or aged BMT recipients subjected to intensive conditioning injury.
Our specific aims are: 1. To determine the thymopoietic and peripheral T cell immune functional effects of TEC sparing agents that target epithelial cell proliferation, inhibit apoptotic cell death, or block the negative regulatory effects of endogenous hormones that disrupt thymopoiesis; 2. To determine whether intracellular pathways required for thymic microenvironmental development or radiation resistance are essential for protecting the thymus from the effects of conditioning regimen injury. These data will lead to clinical trials designed to protect the thymic microenvironment against chemoradiotherapy injury and augment thymopoiesis.
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