Background. Localized delivery of immunosuppressive molecules, limited
to the graft site, may allow transplantation of tissue in the absence
of systemic immunosuppressive agents. We tested whether purified mous
e islets that had been engineered to produce human CTLA4-Ig locally at
the graft site could survive in allogeneic recipients receiving no sy
stemic immunosuppression. Methods. CBA (H2(k)) islets were subjected t
o biolistic (gene gun) transfection with a cDNA encoding human CTLA4-I
g under control of the human cytomegalovirus immediate early promoter.
After 40-48 hr of culture, the transfected islets (500 per recipient)
were transplanted beneath the renal capsule of alloxan-induced diabet
ic BALB/c (H2(d)) recipients. Results. Control grafts (n=10) consistin
g of islets biolistically transfected with the expression plasmid alon
e (i.e., no gene inserted) survived for 12.8+/-3.6 (mean +/- SD) days.
In contrast, islets transfected with CTLA4-Ig (n=12) survived 66.8+/-
61.5 days (P=0.01), with 50% demonstrating functional survival until f
ollow-up was concluded at 50 (n=2), 130 (n=2), or 165 (n=2) days. Immu
nohistochemistry on grafts that survived long term showed well-granula
ted, insulin-positive islets lying adjacent to, but not infiltrated by
, dense aggregates of mononuclear cells. Conclusions. Transfection of
allogeneic mouse islets with human CTLA4-Ig results in prolonged allog
raft survival. Although on histology mononuclear cells are present in
the area of the transfected graft, they do not appear to infiltrate or
destroy the islet graft.