In situ protection against islet allograft rejection by CTLA4Ig transduction.
BACKGROUND
Immunosuppression focused at or near the graft site would reduce the need for systemic immunosuppression thus educing fewer side effects. We investigated whether locally produced CTLA4Ig, mediated by adenovirus (Adv) transduction of mouse islets, would protect allografts and whether such immunosuppression would remain localized.


METHODS
Adv-CTLA4Ig- or Adv-control-transduced islets were grafted under the kidney capsule of fully allogeneic diabetic mice. CTLA4Ig secreted from the grafted islets was detected by enzyme immunoassay of blood or immunohistochemistry of graft sections. Graft survival was monitored by blood glucose measurement. Histologic scores of graft sections stained with Gomori aldehyde fuchsin to detect insulin granules or hematoxylin-eosin to detect inflammation were used to compare grafts placed at different sites within the same mouse.


RESULTS
Adv-CTLA4Ig-transduced islet grafts secreted CTLA4Ig that was detected transiently in the circulation but persistently at the graft site. Survival of these grafts was significantly enhanced compared with control Adv-transduced and untransduced grafts. The kidney graft site availed elucidation of the site of action of CTLA4Ig. Histologic scores indicated that CTLA4Ig-producing grafts were protected by comparison with control grafts on the contralateral kidney. Hence, graft protection was not attributable to general systemic immunosuppression. Indeed, survival of CTLA4Ig-producing grafts was enhanced over control grafts placed at the opposite pole of the same kidney, indicating that graft protection was not solely due to inhibition of priming in the common draining lymph nodes.


CONCLUSIONS
Islet allografts are protected by locally produced CTLA4Ig-disrupting immune interactions at the effector site.
Londrigan
Sarah L
SL
Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Sutherland
Robyn M
RM
Brady
Jamie L
JL
Carrington
Emma M
EM
Cowan
Peter J
PJ
d'Apice
Anthony J F
AJ
O'Connell
Philip J
PJ
Zhan
Yifan
Y
Lew
Andrew M
AM
D000069594:Abatacept; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival; D018796:Immunoconjugates / Q000097:blood / Q000627:therapeutic use*; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D051379:Mice; D014184:Transplantation, Homologous / Q000276:immunology
D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept