Inducing tolerance to MHC-matched allogeneic islet grafts in diabetic NOD mice by simultaneous islet and bone marrow transplantation under nonirradiative and nonmyeloablative conditioning therapy.
BACKGROUND
Human type 1 diabetes is associated with defects in the hematopoietic stem cells. Simultaneous donor islet and bone marrow transplantation may be an ideal therapeutic approach for inducing tolerance to islet allogeneic antigens and restoring self-tolerance to islet autoimmune antigens.


METHODS
Using a nonobese diabetic (NOD) mouse model of human type 1 diabetes, we investigated whether tolerance to MHC-matched allogeneic islet grafts from male nonobese diabetes-resistant (NOR) donors can be induced in female NOD recipients by simultaneous islet and bone marrow transplantation under fludarabine phosphate-based nonmyeloablative and irradiation-free conditioning therapy. Donor-specific chimerism in the peripheral blood of tolerant mice (n=7) was measured by semiquantitative polymerase chain reaction for a male-specific marker (SRY).


RESULTS
Donor-specific tolerance to NOR islet grafts was induced in all diabetic NOD mice after simultaneous islet and bone marrow transplantation and treated with fludarabine phosphate, cyclophosphamide, anti-mouse lymphocyte serum, and rapamycin. At 100 days and 200 days after transplantation, the average percentage of male NOR marker in DNA derived from the peripheral blood of NOD recipients that had long-term islet graft survival was over 10%.


CONCLUSIONS
Our data suggest that this approach may induce donor-specific tolerance in clinical islet transplantation and living-related donor solid organ transplantation.
Wu
Tao
T
Diabetes Institute for Immunology and Transplantation, and Department of Surgery, University of Minnesota, Minneapolis 55455, USA.
Levay-Young
Brett
B
Heuss
Neal
N
Sozen
Hakan
H
Kirchhof
Nicole
N
Sutherland
David E R
DE
Hering
Bernhard
B
Guo
Zhiguang
Z
D000818:Animals; D016026:Bone Marrow Transplantation; D003520:Cyclophosphamide / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery* / Q000628:therapy; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation; D008285:Major Histocompatibility Complex / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology
D007166:Immunosuppressive Agents; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D003520:Cyclophosphamide