Use of Transient CD4 Lymphocyte Depletion to Prolong Transgene Expression of E1-Deleted Adenoviral Vectors

Abstract

E1-deleted adenoviral vectors are increasingly being utilized for in vivo gene transfer. The potential use of these vectors is limited by transient expression of the transgene and a markedly reduced rate of transduction following readministration, presumably due to a host immune response to the vector. We hypothesized that CD4⁺ lymphocytes are necessary to generate an immune response to these vectors and that administration of a depleting anti-CD4 antibody (GK1.5) might prolong transgene expression in vivo. We found that pretreatment of mice with a single injection (transient depletion) or weekly injections of GK1.5 (persistent depletion), markedly prolonged expression of an adenovirus-encoded tumor necrosis factor (TNF) inhibitor or luciferase gene compared to controls. Moreover, mice treated with GK1.5 showed no antiadenoviral antibody response to repeat administration of the vector and a second adenoviral transgene could be expressed in these animals. However, control mice developed a significant neutralizing antibody response that prevented transgene expression with administration of a second adenovirus. These findings demonstrate that manipulation of the host immune response may expand potential applications of gene transfer utilizing adenoviral vectors.

Overview summary

Adenoviral vectors elicit both a humoral antibody and cytotoxic T cell immune response that limits their effectiveness in vivo. Abrogating T cell help by transiently depleting CD4⁺ T cells with an anti-CD4 monoclonal antibody prior to adenovirus prevents both development of a neutralizing antibody and effective cytotoxic T cell response to the vector. Thus, in vivo transgene expression in this model is prolonged and permits repeat administration of another adenoviral vector.