Purpose: To determine if IgM therapy promotes islet allo- and xenograft survival.
Methods: a) 200ug IgM was injected into new onset diabetic NOD mice (n=14) and blood glucose monitored. b) 2000 human islet equivalents (IEQs) were transplanted under the kidney capsule of diabetic BL/6s with and without IgM therapy (IgM (M) n=5; saline (S) n=6). c) 1000 IEQs were transplanted in NOD/scids (M n=4; S n=4). d) 400 Balb/C islets were transplanted under the kidney capsule (M n=6; S n=6); and 350 islets in the portal vein of diabetic BL/6 mice (M n=6; S n=3). e) 5 weeks-old BL/6 and NODs, BL/6- and NOD-VH125 mice and humanized BLT mice received IgM or Saline (5X) following which spleen and bone-marrow cells were analyzed by Flow cytometry.
Results: a) IgM reversed hyperglycemia in 70% of diabetic mice. b) With 2000 IEQS, 5/5 mice in the IgM group returned to normoglycemia, while controls became diabetic in 11±5.5 days (p<0.001). c) Transplantation with 1000 IEQs resulted in restoration of normoglycemia with or without IgM therapy. Removal of islet graft-containing kidney at >60days post-transplant reinstated T1D. d) Following allotransplantation, IgM restored normoglycemia permanently in 6/6 mice. Graft removal at 100 days posttransplant resulted in T1D. Hyperglycemia in controls returned in 10.8±4.7 days. Following intraportal transplantation, all IgM-treated mice were cured. Controls turned diabetic in 6.3±2.5 days. e) IgM mitigated autoimmunity in NODs by reducing % age of marginal zone B cells that perpetuate autoimmunity (p<0.05); by increasing transitional B cell proportions (p<0.01) indicating normalization of B cell homeostatic defects; and inhibiting plasma insulin autoantibody levels (p<0.0001). In NODVH125 mice, IgM eliminated insulin binding B cell population (p<0.0001) and in humanized BLT mice, hIgM therapy expanded the Helios+Foxp3+Treg population.
Conclusion: IgM therapy reversed T1D and promoted permanent islet graft survival indicating its clinical relevance for T1D.
M. Ma: None. K.L. Brayman: None. P. Chhabra: None.
American Diabetes Association (1-17-IBS-244 to K.L.B.); University of Virginia