Autoimmune diabetes recurrence is in part responsible for islet graft destruction in type 1 diabetic individuals. The aim of the present study was to design treatment modalities able to prevent
autoimmune diabetes recurrence after
islet transplantation in spontaneously diabetic NOD mice. In order to avoid
confusion between
autoimmune diabetes recurrence and allograft rejection, we performed syngeneic
islet transplantations in spontaneously diabetic NOD mice. Mice were treated with mouse
interferon-beta (IFN-beta, 1 x 105 IU/day), a new 14-epi-1,25-(OH)2D3-analogue (
TX 527, 5 microg/kg/day) and
cyclosporin A (CsA, 7.5 mg/kg/day) as single substances and in combinations. Treatment was stopped either 20 days (IFN-beta and CsA) or 30 days (
TX 527) after
transplantation.
Autoimmune diabetes recurred in 100% of control mice (MST 11 days). None of the mono-
therapies significantly prolonged islet graft survival. Combining CsA with
TX 527 maintained graft function in 67% of recipients as long as treatment was given (MST 31 days, P < 0.01 versus controls). Interestingly, 100% of the IFN-beta plus TX 527-treated mice had normal
blood glucose levels during treatment, and even had a more pronounced prolongation of graft survival (MST 62 days, P < 0.005 versus controls).
Cytokine mRNA analysis of the grafts 6 days after
transplantation revealed a significant decrease in
IL-2, IFN-gamma and
IL-12 messages in both IFN-beta plus
TX 527- and CsA plus TX 527-treated mice, while only in the IFN-beta with
TX 527 group were higher levels of
IL-10 transcripts observed. Therefore, we conclude that a combination of IFN-beta and
TX 527 delays
autoimmune diabetes recurrence in islet grafts in spontaneously diabetic NOD mice.