*Purpose: To investigate if islet allo- and xenotransplant rejection is mitigated by IgM immunotherapy.

*Methods: a) New onset diabetic NOD mice (n=14) were treated with IgM (200 μg; Day1,3 &5) and blood glucose monitored. b) For measuring islet viability, human islets were stained with Propidium iodide/Fluoroscein diacetate. 2000 islet equivalents (IEQs) were transplanted under the renal capsule of diabetic C57BL/6 mice. Graft recipients received 200mg IgM I.P. on Day -2 pretransplant followed by 100mg on Days 2, 7, 14 & 21 post-transplant (IgM n=5; saline n=6). c) As controls, 1000 IEQs were transplanted in immunodeficient NOD/scids (IgM n=4; saline n=4). d) 400 Balb/C islets were allotransplanted under renal capsule of diabetic BL/6 mice (IgM n=6; control n=6). e) 400 BL/6 islets were syngeneically transplanted intra-portal vein in BL/6 mice (IgM n=6; control n=3). f) 5wks-old BL/6 and NOD mice, BL/6- and NOD-VH125 mice, and humanized BLT mice received 100ug IgM on Day1, and 50ug on Days 3,5,7 &10. Spleen and bone-marrow cell harvest on Day13 was followed by Flow cytometry analysis.

*Results: a) IgM reversed hyperglycemia in 70% of diabetic mice, whilst IgM derived from prediabetic NOD donors did not reverse diabetes. b) With 2000 IEQS, 5/5 mice in IgM group returned to normoglycemia following xenotransplantation. Control mice (n=6) returned to hyperglycemia in 6.1±2.5 days (p<0.001). c) 1000 IEQs xenotransplanted into diabetic NOD/scid mice resulted in return to normoglycemia both with and without IgM therapy. Removal of islet graft-containing kidney at >60days post-transplant resulted in return of diabetes. d) Following allotransplantation, IgM restored normoglycemia permanently in 6/6 mice. Removal of graft-containing kidney at 100 days posttransplant reinstated diabetes. Control mice returned to hyperglycemia in 6.3±2.8 days days. e) Following intraportal transplantation, normoglycemia was restored in 6/6 IgM-treated mice. Controls turned diabetic in 4±1.7 days. f) IgM reduced the percentage of marginal zone B cells (p<0.05) and increased transitional B cell proportions (p<0.01) indicating normalization of B cell homeostatic defects; and inhibited plasma insulin autoantibody levels (p<0.0001). Human IgM therapy expanded the Helios⁺Foxp3⁺Treg population in humanized BLT mice.

*Conclusions: IgM therapy restores immune homeostasis, diminishes autoreactivity, and promotes permanent islet graft survival indicating its clinical relevance for cure of T1D.

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