Targeted bone marrow radioablation with 153Samarium-lexidronam promotes allogeneic hematopoietic chimerism and donor-specific immunologic hyporesponsiveness.
BACKGROUND
Transplantation tolerance, defined as acceptance of a graft by an otherwise fully immunocompetent host, has been an elusive goal. Although robust tolerance has been achieved by the induction of stable hematopoietic chimerism after bone marrow transplantation, lethal or sublethal radiation conditioning used to induce long-term chimerism precludes its clinical use. We studied whether targeted delivery of radiation to bone marrow could allow for bone marrow cell (BMC) engraftment, chimerism, and donor-specific tolerance in the absence of the side effects associated with external irradiation.


METHODS
We administered a radioactive bone-seeking compound (Samarium-Lexidronam, Quadramet, Berlex Laboratories, Wayne, NJ) together with transient T-cell costimulatory blockade to recipient mice. Allogeneic BMCs were given 7 or 14 days after preconditioning. Costimulatory blockade was obtained by the use of an anti-CD154 antibody for 4 weeks. Chimerism was assessed by flow cytometry. Mice then received donor-specific and third-party skin grafts. Graft survival was analyzed with mechanisms of donor-specific hyporesponsiveness.


RESULTS
High levels of stable chimerism across an allogeneic barrier were achieved in mice by a single administration of Samarium-Lexidronam, transient T-cell costimulatory blockade, and BMC transplantation. A large percentage of chimeric animals retained donor-derived skin grafts for more than 120 days without requiring additional immunosuppression, suggesting that harsh cytotoxic preconditioning is not necessary to achieve stable chimerism and donor specific hyporesponsiveness. Analysis of the T-cell repertoire in chimeras indicates T-cell deletional mechanisms.


CONCLUSIONS
These data broaden the potential use of BMC transplantation for tolerance induction and argue for its potential in treating autoimmune diseases.
Inverardi
Luca
L
Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida, USA.
Linetsky
Elina
E
Pileggi
Antonello
A
Molano
R Damaris
RD
Serafini
Aldo
A
Paganelli
Giovanni
G
Ricordi
Camillo
C
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000528:radiation effects; D016026:Bone Marrow Transplantation / Q000000981:diagnostic imaging / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology / Q000528:radiation effects; D006085:Graft Survival / Q000276:immunology / Q000528:radiation effects; D007108:Immune Tolerance / Q000528:radiation effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019653:Myeloablative Agonists / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011877:Radionuclide Imaging; D016038:Skin Transplantation / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology*
D019653:Myeloablative Agonists; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; C061972:samarium Sm-153 lexidronam