Gene Transfer to the Thymus A Means of Abrogating the Immune Response to Recombinant Adenovirus

Induction of central tolerance by intrathymic inoculation of adenoviral antigens into the host thymus permits long-term gene therapy in Gunn rats.

“…Our results are different from those in a recent report that demonstrated that injection of adenovirus infected cells into the mouse thymus induced cellular, but not humoral tolerance (31). In that study, direct injection of the virus into the thymus resulted in production of a marked antiadenovial antibody response but no CTL response against the adenovirus (31).…”

“…Our results are different from those in a recent report that demonstrated that injection of adenovirus infected cells into the mouse thymus induced cellular, but not humoral tolerance (31). In that study, direct injection of the virus into the thymus resulted in production of a marked antiadenovial antibody response but no CTL response against the adenovirus (31). A possible explanation for the different findings may be that a significant degree of extravasation of the virus occurred during the intrathymic injection in the mouse, as indicated by viral expression in extrathymic tissues even when the virus was injected into the thymus only (31).…”

Induction of stable prenatal tolerance to β-galactosidase by in utero gene transfer into preimmune sheep fetuses

“…Recent reports have demonstrated that tolerance to vectors and transgene products could be induced if lymphocytes underwent thymic selection in the presence of vector antigens [48][49][50][51][52] and that this tolerance led to a prolongation of transgene expression. For example, DeMatteo and colleagues 48,49 showed that intrathymic inoculation of neonatal mice with a recombinant adenoviral vector encoding the lacZ gene during the period prior to T-cell maturation resulted in the induction of host tolerance to the adenoviral vector and the transgene product.…”

“…For example, DeMatteo and colleagues 48,49 showed that intrathymic inoculation of neonatal mice with a recombinant adenoviral vector encoding the lacZ gene during the period prior to T-cell maturation resulted in the induction of host tolerance to the adenoviral vector and the transgene product. Furthermore, when these tolerized mice were injected intravenously as adults with the same adenoviral vector, they exhibited an impaired adenovirusspecific cytotoxic T-lymphocyte response, which allowed prolonged ␤-gal expression to be achieved for up to 260 days.…”

Expression of Coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers

“…1,3,16,19 Systemic intravenous vector injection which is a most convenient way of vector application leads mainly to expression of the transgene in liver. 16,20 One possible way to achieve efficient transgene expression into other organs is injection of the vector directly into or near the target site such as has been demonstrated for skeletal muscle, 20,21 heart, [22][23][24] blood vessels, 25,26 lung, 27,28 brain, 18,29 intestine, 30 thymus, 31 eye, 4,32 cochlea 10 and salivary glands. 33 Direct injection is accompanied, however, by narrowly localized transgene expression along the needle track and injury to tissues surrounding the injection site.…”