Submitted February 27, 2006
Accepted April 7, 2006
Simple conditioning with mono-specific
CD4+CD25+ regulatory T cells for
bone marrow engraftment and tolerance to multiple gene
products
David-Alexandre Gross*, Pascal Chappert, Marylene Leboeuf, Virginie Monteilhet, Laetitia Van Wittenberghe, Olivier Danos, and Jean Davoust
GENETHON, CNRS UMR 8115, 1bis, rue de l'Internationale, France
* Corresponding author; email: gross{at}genethon.fr.
A major impediment to gene replacement therapy is immune elimination of genetically modified cells. In principle, this can be dealt with by inducing a strong, specific and enduring tolerance through engraftment of transgene modified autologous bone marrow (BM). Since usual myeloablation and/or immunosuppression are risk factors in most pathologies, we assessed the potential of mono-specific CD4+CD25+ regulatory T cells (Tregs) to engraft minor-mismatched BM without preconditioning. We found here that as few as 5x104 Tregs directed to the male DBY protein promote the engraftment of foreign male BM into sex mismatched female hosts, establishing sustained chimerism in all hematopoeitic compartments. We achieved concomitantly strong tolerance to all foreign antigens expressed in the BM, likely occurring through induction of anergy and/or deletion of anti-donor T cells. Chimerism was obtained in thymectomized mice too, underlining the major role of peripheral tolerance mechanisms in our system. This allowed us to engraft gene-modified tissues, while preserving full immunocompetence to third party antigens. Our results demonstrate that very few donor-specific Tregs are effective as the sole conditioning, to induce mixed molecular chimerism and long-term tolerance to multiple foreign antigens.
