Murine Model of Thymic Damage and Recovery Following Sublethal Ionizing Radiation

Abstract

<p>The thymus is the primary lymphoid organ responsible for generation of functional T lymphocytes. The loss of thymic function, either as a consequence of physiological senescence or the result of disease- and/or treatment-related pathology, affects individual¡¯s capacity to maintain a broad T cell antigen receptor repertoire. In consequence, the ability to mount an efficient adaptive immune response may become restricted. Currently, there are no available treatments to protect against acute thymic involution, and little is known about the mechanisms that drive thymic involution and recovery. The induction of thymic involution and the delay in thymus recovery emphasize the need to identify the mechanisms that drive stress-induced acute thymic involution, and the need to develop therapeutics to block involution and/or enhance thymus recovery during acute stress events. While many studies have characterized poor immune recovery due to high/lethal doses of radiation, the overall response of the immune system after exposure to a sublethal dose of radiation is unclear. The goal of this research was to develop a murine model of acute thymic involution induced by sublethal irradiation where damage and recovery effects induced by radiation could be examined. </p><p> We present here our two-phase irradiation-induced (¡Ü 125 cGy, 250 cGy and 550 cGy) thymic involution model in young BALB/c mice. We observed a dramatic dose-dependent impact of irradiation on thymopoiesis on day 7. By day 35 there was spontaneous recovery of thymus, and restoration of the peripheral lymphoid compartments. Thymus function was monitored by thymus weight, cellularity, and TCR gene re-arrangement (mTREC). During the damage phase our studies demonstrated decreased expression of thymostimulatory cytokine, KGF, and loss of active TCR gene rearrangement following radiation exposure in young mice. An increase of KGF levels correlated with the overall spontaneous recovery observed. Thus, suggesting a critical role of thymic-stromal derived KGF in promoting stroma/thymocyte crosstalk to mediate thymus recovery. </p><p> Overall, our characterization of our model provided a useful estimate of thymic response to stress induced by irradiation and our findings may provide a model to a better future understanding of mechanisms involved in thymus recovery from damage and inform development of strategies to restore thymic function in the stressed-induced acute thymic involution.</p>