Anti-T Cell Receptor Antibody Prolongs Transgene Expression and Reduces Lung Inflammation after Adenovirus-Mediated Gene Transfer

Abstract

Replication-deficient ΔE1a-E3 adenovirus mediates efficient gene transfer to the mouse lung; however it induces a host immune response mediated, in part, by T cells. This immune response is associated with loss of transgene expression. Monoclonal antibodies (mAb) against the T cell receptor (TCR) complex can inhibit both CD4⁺ and CD8⁺ T cell responses in vivo and are the most potent anti-T cell agents in clinical use. To determine whether such mAbs can be used to prolong adenovirus-mediated transgene expression, the vector Av1Luc1 (ΔE1a-E3 recombinant adenovirus encoding the firefly luciferase gene) was administered intratracheally to C57BL/6 mice on day 0. Three days prior to adenovirus administration (day –3), mice were treated with a single i.p. injection of the anti-TCR mAb H57. Controls received phosphate-buffered saline. Animals were sacrificed on days 3, 14, 28, and 56 and lungs were assessed for transgene expression and histopathology. Luciferase activity decreased markedly in the controls by day 14, but was maintained at high levels in animals receiving anti-TCR mAb. A mild, focal, predominantly neutrophilic inflammation was observed in the alveoli of all mice 3 days after virus administration. In PBS-treated controls, this inflammation progressed to a moderate to severe multifocal, perivascular and peribronchiolar lymphoid infiltration at 14 days. B cells and T cells were present in approximately equal numbers, with CD4⁺ T cells predominating over CD8⁺ T cells by 3- to 28-fold. Treatment with H57 resulted in near-complete prevention of the lymphocytic inflammatory infiltrate and increased luciferase activity throughout the 56-day study period, in association with TCR modulation and T cell depletion. Thus, anti-TCR mAb decreases inflammation and prolongs gene expression following adenovirus-mediated gene transfer. Intratracheal injection of Av1Luc1, an E1a-E3-deleted recombinant Ad5 adenovirus, to C57BL/6 mice results in transient transgene expression, associated with a peribronchial and perivascular inflammatory response. B cells and CD4⁺ T cells predominate in these lesions. This inflammatory response is blocked by administration of the anti-TCR mAb H57, with resultant prolonged transgene expression over a 56-day observation period.