A substantial level of donor hematopoietic chimerism is required to protect donor-specific islet grafts in diabetic NOD mice.
BACKGROUND
Mixed chimerism can induce tolerance to alloantigens and restore self-tolerance to autoantigens, thereby permitting islet transplantation. However, the minimal level of donor chimerism that is required to prevent islet allograft rejection and recurrence of autoimmune diabetes has not been established.


METHODS
We investigated whether allogeneic Balb/c donor chimerism can be induced in C57BL/6 mice, in prediabetic NOD mice, and in diabetic NOD mice after transplantation of a modest dose of bone marrow by using purine nucleoside analogue, fludarabine phosphate and cyclophosphamide conditioning therapy, followed by short-term anti-CD40 ligand monoclonal antibody and rapamycin posttransplant treatment. We also investigated whether the induced donor chimerism is sufficient to prevent the onset of diabetes in prediabetic NOD mice and protect donor islet grafts in diabetic NOD mice.


RESULTS
Allogeneic donor chimerism could be induced under the authors' approach that is nonmyeloablative and radiation-free. Diabetes onset was prevented in chimeric prediabetic NOD mice. The induction of mixed chimerism protected donor-specific islet grafts in diabetic NOD mice. At 60 days after islet transplantation, all donor Balb/c islet grafts survived in diabetic NOD mice whose level of donor-derived lymphocytes was higher than 30% at the time of islet transplantation (n=8). In contrast, Balb/c islet grafts were rejected in five of seven diabetic NOD mice whose level was lower than 30%.


CONCLUSIONS
Our data demonstrate that a donor lymphocyte chimerism (>30%) at the time of islet transplantation is required to protect donor-specific islet grafts, and indicate that a strictly non-irradiation-based protocol can be used to achieve this goal.
Guo
Zhiguang
Z
Diabetes Institute for Immunology and Transplantation, and Department of Surgery, MMC 195, University of Minnesota, 420 Delaware Street S.E., Minneapolis, MN 55455. zhiguang@tc.umn.edu
Wu
Tao
T
Sozen
Hakan
H
Pan
Yisheng
Y
Heuss
Neal
N
Kalscheuer
Hannes
H
Sutherland
David E R
DE
Blazar
Bruce R
BR
Hering
Bernhard J
BJ
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D003520:Cyclophosphamide / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D005260:Female; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation; D008214:Lymphocytes / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D014019:Tissue Donors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D003520:Cyclophosphamide