Simple conditioning with monospecific CD4+CD25+ regulatory T cells for bone marrow engraftment and tolerance to multiple gene products.
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). Because usual myeloablation and/or immunosuppression are risk factors in most pathologies, we assessed the potential of monospecific CD4(+)CD25(+) regulatory T cells (Tregs) to engraft minor-mismatched BM without preconditioning. We found that as few as 5 x 10(4) 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 antidonor 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.
Gross
David-Alexandre
DA
Genethon, CNRS UMR 8115, 1bis, rue de l'Internationale, BP 60, 91002 Evry Cedex, France. gross@genethon.fr
Chappert
Pascal
P
Leboeuf
Marylene
M
Monteilhet
Virginie
V
Van Wittenberghe
Laetitia
L
Danos
Olivier
O
Davoust
Jean
J
D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002678:Chimera / Q000276:immunology; D053487:DEAD-box RNA Helicases; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D011506:Proteins / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015778:Minor Histocompatibility Antigens; D011506:Proteins; D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C115600:Ddx3y protein, mouse; D053487:DEAD-box RNA Helicases