Long-term islet graft survival in NOD mice by abrogation of recurrent autoimmunity.
Islet transplantation has great potential for curing type 1 diabetes; however, long-term islet survival using conventional immunosuppression remains elusive. We present a novel strategy for inducing long-lasting islet graft survival in diabetic NOD mice in the absence of posttransplant immunosuppression by initial treatment with antilymphocyte serum (ALS) followed by coadministration of donor pancreatic lymph node cells (PLNCs). When treated with ALS/PLNC, diabetic NOD mice become normoglycemic and tolerated minor antigen-disparate islet grafts for >100 days and syngeneic islet grafts indefinitely. Donor T-cells are required for graft prolongation, and tolerant hosts have long-term donor T-cell chimerism. Strikingly, host autoreactive T-cells from mice with long-surviving islet grafts predominantly produce interleukin-4, whereas autoreactive T-cells from mice that rejected their islet grafts predominantly produce interferon-gamma. We thus demonstrate a clinically relevant approach for ablation of recurrent autoimmunity in islet transplantation, involving donor lymphocyte-driven alteration of pathogenic autoreactive T-cells.
Shi
Qixin
Q
Division of Transplantation, Department of Surgery, University of Maryland School of Medicine, 29 South Greene St., Baltimore, MD 21201, USA.
Wang
Donghua
D
Hadley
Gregg A
GA
Bingaman
Adam W
AW
Bartlett
Stephen T
ST
Farber
Donna L
DL
D000818:Animals; D000961:Antilymphocyte Serum / Q000494:pharmacology; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000601:surgery*; D006085:Graft Survival / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D018183:Transplantation Chimera / Q000276:immunology
D000961:Antilymphocyte Serum; D015847:Interleukin-4; D007371:Interferon-gamma