Co-graft of allogeneic immune regulatory neural stem cells (NPC) and pancreatic islets mediates tolerance, while inducing NPC-derived tumors in mice.
BACKGROUND
Data available on the immunomodulatory properties of neural stem/precursor cells (NPC) support their possible use as modulators for immune-mediated process. The aim of this study was to define whether NPC administered in combination with pancreatic islets prevents rejection in a fully mismatched allograft model.


RESULTS
Diabetic Balb/c mice were co-transplanted under the kidney capsule with pancreatic islets and GFP(+) NPC from fully mismatched C57BL/6 mice. The following 4 groups of recipients were used: mice receiving islets alone; mice receiving islets alone and treated with standard immunosuppression (IL-2Ralpha chain mAbs + FK506 + Rapamycin); mice receiving a mixed islet/NPC graft under the same kidney capsule (Co-NPC-Tx); mice receiving the islet graft under the left kidney capsule and the NPC graft under the right kidney capsule (NPC-Tx). Our results demonstrate that only the co-transplantation and co-localization of NPC and islets (Co-NPC-Tx) induce stable long-term graft function in the absence of immunosuppression. This condition is associated with an expansion of CD4(+)CD25(+)FoxP3(+) T regulatory cells in the spleen. Unfortunately, stable graft function was accompanied by constant and reproducible development of NPC-derived cancer mainly sustained by insulin secretion.


CONCLUSIONS
These data demonstrate that the use of NPC in combination with islets prevents graft rejection in a fully mismatched model. However, the development of NPC-derived cancer raises serious doubts about the safety of using adult stem cells in combination with insulin-producing cells outside the original microenvironment.
Melzi
Raffaella
R
San Raffaele Diabetes Research Institute (HSR-DRI), Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.
Antonioli
Barbara
B
Mercalli
Alessia
A
Battaglia
Manuela
M
Valle
Andrea
A
Pluchino
Stefano
S
Galli
Rossella
R
Sordi
Valeria
V
Bosi
Emanuele
E
Martino
Gianvito
G
Bonifacio
Ezio
E
Doglioni
Claudio
C
Piemonti
Lorenzo
L
D053687:Adult Stem Cells; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D006084:Graft Rejection / Q000517:prevention & control*; D007515:Islets of Langerhans; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000209:etiology / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology; D009474:Neurons; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous