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Reactive Oxygen Intermediates During Programmed Cell Death Induced in the Thymus of the Ts(17¹⁶)65Dn Mouse, a Murine Model for Human Down’s Syndrome¹

Jesús E. Paz-Miguel^*, Reyes Flores, Pablo Sánchez-Velasco^*, Gonzalo Ocejo-Vinyals^*, Juan Escribano de Diego^*, Jacobo López de Rego and Francisco Leyva-Cobián^2,*

^* Servicio de Inmunología, Hospital Universitario "Marqués de Valdecilla," Instituto Nacional de la Salud, Santander, Spain; and Departamento de Biología Celular, Facultad de Medicina, Universidad Complutense, Madrid, Spain

Down’s syndrome (DS) is one of the most frequent genetic disorders in humans. It has been suggested that overexpression of copper-zinc superoxide dismutase (SOD-1) in DS may be involved in some of the abnormalities observed, mainly neurodegenerative and immunopathological processes. One of the consequences is early thymic involution. Recently, Ts(17¹⁶)65Dn mice (Ts65Dn mice), made segmentally trisomic for a chromosome 16 segment, fulfill the criteria for a DS model. To study the possible role of SOD-1 overexpression in thymocyte biology, we analyzed the role of reactive oxygen intermediates during in vivo and in vitro programmed cell death (PCD) induced in the thymus of Ts65Dn mice. Our main findings can be summarized as follows. Ts65Dn thymuses exhibit greater PCD activity than controls, as ascertained by a combination of morphological, histochemical, and ultrastructural procedures. Ts65Dn thymocytes were highly susceptible to PCD induced by both LPS (in vivo) and dexamethasone, a synthetic glucocorticoid agonist (both in vivo and in vitro). Thymus abnormalities were probably caused by SOD-1 hyperexpression in Ts65Dn cells, in that reactive oxygen intermediate generation (specifically H₂O₂ production) is enhanced in thymocytes and clearly correlates with apoptosis. Similarly, oxidative injury correlated with the formation of lipid peroxidation by-products and antioxidants which partly inhibit PCD in thymocytes.

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