ADENOVIRAL VECTOR-MEDIATED GENE-EXPRESSION IN THE NERVOUS-SYSTEM OF IMMUNOCOMPETENT WISTAR AND T-CELL-DEFICIENT NUDE RATS - PREFERENTIAL SURVIVAL OF TRANSDUCED ASTROGLIAL CELLS IN NUDE RATS

In the present paper, we examined the effect of the adenoviral vector dosage, the role of T cells, and the influence of the presence of repl ication-competent adenovirus (RCA) in adenoviral vector stocks, on the efficacy of adenoviral vector-directed transgene expression in the fa cial nucleus of immunocompetent Wistar and athymic nude rats. A small number of motor neurons and glial cells was transduced at low dosages of viral vector (1 x 10(6) pfu) and in the absence of RCA, and transge ne-expressing cells persisted throughout the 3-week period of observat ion. Intraparenchymal infusion of 2 x 10(7) pfu of a recombinant adeno viral vector free of RCA was required for optimal transduction of faci al motor neurons. In Wistar rats, a biphasic immune response occurred at higher dosages of the vector (5 x 10(6) and 2 x 10(7) pfu) that was characterized by early infiltration of macrophages and the occurrence of T cells during the second week after injection of the vector. The immune response was associated with the loss of transduced neural cell s. In nude rats, administration of an adenoviral vector free of RCA re sulted in a macrophage response comparable to that in the Wistar rat a nd long-term survival of transduced astroglial cells. However, transdu ced motor neurons degenerated according to a similar time course as ob served in Wistar rats. Small amounts of RCA (2 x 10(5) pfu) injected w ith 2 x 10(7) pfu recombinant viral vector particles resulted in an ac celerated T cell response and a rapid elimination of transduced cells within 1 week in Wistar rats, whereas in nude rats transgene expressio n continued during this period. Taken together, these observations sug gest that at the high viral vector loads necessary to achieve optimal transduction of the facial nucleus, T cells play a role in the degener ation of adenoviral vector-transduced astroglial cells. The adverse ef fects on neurons appear to be due to the observed inflammatory respons e or to direct adenoviral vector toxicity.