A murine model for genetic manipulation of the T cell compartment

The expression of exogenous genes in long-lived primary T cells is potentially beneficial for the treatment of various diseases including cancer, AIDS, genetic defects of the lymphoid compartment, and systemic enzyme deficiencies such as hemophilia. One approach for genetic modification of T cells is to introduce therapeutic genes into hematopoietic stem cells that would give rise to cells of the lymphoid lineage. Efficient gene transfer and expression in stem cells is often problematic, however. A more direct approach is to introduce the genes into mature primary T lymphocytes since the transferred genes can be maintained and expressed for long periods by long-lived peripheral T cells. In this report, we describe the adoptive transfer into SCID mice of both murine and human primary T cells that have been efficiently transduced with exogenous genes. Primary murine T cells transduced with a retroviral vector containing the human adenosine deaminase (ADA) gene persisted for at least 5 months in lymphoid organs of SCID mice, continuously expressing the exogenous gene. Primary human T cells were also used as target cells for transfer of the beta-galactosidase (lacZ) gene. Expression of the lacZ gene could be detected in over 20% of the transduced primary T cells before adoptive transfer into SCID mice. Transduced human T cells were injected into SCID mice intraperitoneally (ip), and the beta-galactosidase activity could be detected in cells collected from peritoneal exudate washes of recipient mice 6 weeks post-injection. These results demonstrate the availability of a murine model in which the long-term effects of expression of exogenous genes in both murine and human T cells can be tested.