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 Blood, 15 September 2007, Vol. 110, No. 6, pp. 1788-1796.
Prepublished online as a Blood First Edition Paper on May 10, 2007; DOI 10.1182/blood-2006-11-059873.

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GENE THERAPY

The immune response to lentiviral-delivered transgene is modulated in vivo by transgene-expressing antigen-presenting cells but not by CD4+CD25+ regulatory T cells

Andrea Annoni1, Manuela Battaglia1, Antonia Follenzi1,3, Angelo Lombardo1, Lucia Sergi-Sergi1, Luigi Naldini1,2, and Maria-Grazia Roncarolo1,2

1 San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy; 2 Università Vita-Salute San Raffaele, Milan, Italy; and 3 Albert Einstein College of Medicine, Bronx, NY

Systemic delivery of lentiviral vector (LV) in immunocompetent mice leads to efficient in vivo cell transduction and expression of the encoded protein under the control of the ubiquitous promoter of human cytomegalovirus (CMV). However, antitransgene immune response results in clearance of transduced cells 4 weeks after injection. T regulatory cells (Tregs), which have been demonstrated to control immune responses in vivo, were tested for their ability to suppress antitransgene response leading to stable long-term expression. Adoptive transfer of natural CD4+CD25+ Tregs (nTregs) isolated from wild type (wt) mice or from transgene tolerant transgenic (tg) mice did not suppress the antitransgene immune response after LV delivery. These data demonstrate that neither increasing the endogenous pool of natural Tregs nor transferring nTregs selected in a transgene-expressing thymus can modulate the immune response and mediate sustained transgene expression. Conversely, adoptive transfer of antigen-presenting cells (APCs) isolated from transgene-tolerant tg mice efficiently reduced the immune response leading to stable LV-encoded protein expression in vivo. Reduction of CD8+ effector T cells was observed in LV-treated mice coinjected with transgene-expressing APCs compared with control mice. These data indicate that antitransgene immune response can be modulated by transgene-expressing APCs possibly through deletion of effector T cells.


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