BACKGROUND: We previously established a clinically relevant strategy to abrogate recurrent autoimmunity and enable long-term islet graft survival, involving antilymphocyte serum (ALS)-depletion of recipient T cells and intraportal administration of donor pancreatic lymph node cells (PLNCs) along with islet grafts. In this study, we investigated whether Th2 cytokines were required for the tolerizing ability of ALS/PLNC treatment in islet transplantation. METHODS: ALS-treated diabetic NOD recipient mice, and NOD recipient mice deficient in interleukin 4 (IL-4-/-) or 10 (IL-4/10-/-) were transplanted with NOR or NOD.scid islets intraportally along with donor PLNC. Blood glucose levels were monitored to access graft function, sections of graft-bearing livers were histologically examined, and ELISPOT assays were used to assess cytokine profile and frequency of islet-reactive CD4 T cells. RESULTS: We found that ALS/PLNC was not effective in prolonging islet graft survival in diabetic NOD hosts deficient in either IL-4 (NOD.IL-4-/-) or in IL-4 and IL-10 (NOD.IL4-/-/10-/-) (mean survival time, 36 days), contrasting the long-term survival of islet grafts in wild-type NOD mice (mean survival time, > 80 days). In contrast, PLNC deficient in IL-4 promoted long-term graft survival in wild-type NOD hosts similar to that in wild-type PLNC. In wild-type NOD recipients of either wild-type PLNC or IL-4-/- PLNC, the host autoantigen-specific CD4 T cells produced predominately IL-4 coincident with long-term graft survival, whereas, in NOD.IL-4-/- recipients with rejected grafts, the autoreactive T cells produced interferon gamma and low amounts of IL-4. CONCLUSIONS: These data demonstrate that abrogation of recurrent autoimmunity requires host IL-4 and that manipulation of the autoreactive cytokine profile in long-term diabetes may be an effective strategy for islet transplant therapies.
BACKGROUND: We previously established a clinically relevant strategy to abrogate recurrent autoimmunity and enable long-term islet graft survival, involving antilymphocyte serum (ALS)-depletion of recipient T cells and intraportal administration of donorpancreatic lymph node cells (PLNCs) along with islet grafts. In this study, we investigated whether Th2 cytokines were required for the tolerizing ability of ALS/PLNC treatment in islet transplantation. METHODS:ALS-treated diabetic NOD recipient mice, and NOD recipient mice deficient in interleukin 4 (IL-4-/-) or 10 (IL-4/10-/-) were transplanted with NOR or NOD.scid islets intraportally along with donor PLNC. Blood glucose levels were monitored to access graft function, sections of graft-bearing livers were histologically examined, and ELISPOT assays were used to assess cytokine profile and frequency of islet-reactive CD4 T cells. RESULTS: We found that ALS/PLNC was not effective in prolonging islet graft survival in diabetic NOD hosts deficient in either IL-4 (NOD.IL-4-/-) or in IL-4 and IL-10 (NOD.IL4-/-/10-/-) (mean survival time, 36 days), contrasting the long-term survival of islet grafts in wild-type NOD mice (mean survival time, > 80 days). In contrast, PLNC deficient in IL-4 promoted long-term graft survival in wild-type NOD hosts similar to that in wild-type PLNC. In wild-type NOD recipients of either wild-type PLNC or IL-4-/- PLNC, the host autoantigen-specific CD4 T cells produced predominately IL-4 coincident with long-term graft survival, whereas, in NOD.IL-4-/- recipients with rejected grafts, the autoreactive T cells produced interferon gamma and low amounts of IL-4. CONCLUSIONS: These data demonstrate that abrogation of recurrent autoimmunity requires host IL-4 and that manipulation of the autoreactive cytokine profile in long-term diabetes may be an effective strategy for islet transplant therapies.