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 Blood, 15 March 2006, Vol. 107, No. 6, pp. 2286-2293.
Prepublished online as a Blood First Edition Paper on November 15, 2005; DOI 10.1182/blood-2005-03-1172.

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GENE THERAPY

Tolerance induction by lentiviral gene therapy with a nonmyeloablative regimen

Noboru Mitsuhashi, Jacqueline Fischer-Lougheed, Irina Shulkin, Annette Kleihauer, Donald B. Kohn, Kenneth I. Weinberg, Vaughn A. Starnes, and Mary Kearns-Jonker

From the Division of Cardiothoracic Surgery, Department of Cardiothoracic Surgery, Transplantation Biology Research Laboratory, Children's Hospital Los Angeles and Keck School of Medicine; and the Division of Research Immunology and Bone Marrow Transplantation, Departments of Pediatrics, Molecular Microbiology, and Immunology, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA.

Antibodies (Abs) directed at the Gal{alpha}1,3Galbeta1,4GlcNAc-R ({alpha}Gal) carbohydrate epitope initiate xenograft rejection. Previously, we have shown that bone marrow transplantation (BMT) with lentivirus-mediated gene transfer of porcine {alpha}1,3 galactosyltransferase (GalT) is able to induce tolerance to {alpha}Gal-expressing heart grafts following a lethal dose of irradiation. Here we show the first demonstration of permanent survival of {alpha}Gal+ hearts following transplantation with autologous, lentivirus-transduced BM using a nonmyeloablative regimen. Autologous BM from GalT knockout (GalT–/–) mice was transduced with a lentiviral vector expressing porcine GalT and transplanted into sublethally irradiated (3 Gy) GalT–/– mice. Chimerism in the peripheral blood cells (PBCs) remained low but was higher in the BM, especially within the stromal cell population. Mice reconstituted with GalT did not produce anti-{alpha}Gal Abs over time. We immunized these mice with {alpha}Gal-expressing cells and assessed humoral immune responses. Anti-{alpha}Gal xenoantibodies were not produced in mice reconstituted with GalT, but normal Ab responses to other xenoantigens were detected. Mice reconstituted with GalT accepted {alpha}Gal+ heart grafts over 100 days. Transduction with lentiviral vectors results in chimerism at levels sufficient to induce long-term tolerance under nonmyeloablative conditions.


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