*Purpose: To investigate if IgM therapy mitigates islet allo- and xenotransplant rejection and promotes permanent islet survival.

*Methods: 1) New onset diabetic NOD mice (n=14) were treated with IgM (200 μg on Day1, 3, and 5) and blood glucose (BG) monitored serially. 2) Human islets were isolated at the UVA GMP islet isolation facility using a modified Ricordi technique. PI/FDA and Dithazone staining were done to measure islet viability and visualize islets. 2000 human islet equivalents (IEQs) were transplanted under the kidney capsule of Strep-induced diabetic C57BL/6. Islet recipients received 200mg IgM I.P. on Day -2 pretransplant followed by 100mg on Day 2, 7, 14 and 21 post-transplant (IgM n=5; saline n=6). 3) 1000 IEQs were similarly transplanted in NOD/scid mice (IgM n=4; saline n=4). 4) 400 Balb/C islets were transplanted under the kidney capsule of diabetic BL/6 mice (IgM n=6; control n=6). 5) 350 Balb/C islets were transplanted in the portal vein of BL/6 mice (IgM n=6; control n=3). 6) 5wks-old BL/6 and NOD mice, BL/6- and NOD-VH125 mice, and humanized BLT mice received 100ug IgM on Day1 followed by 50ug on Days 3,5,7 and 10. Spleen and bone-marrow cell harvest on Day13 was followed by Flow cytometry analysis.

*Results: 1) IgM reversed hyperglycemia in 70% of diabetic mice (monitored for 2 months post treatment). IgM derived from prediabetic NOD donors did not reverse diabetes. 2) With 2000 human IEQS, 5/5 mice in IgM group returned to normoglycemia with BG≤200mg/dL following xenotransplantation. Control mice returned to hyperglycemia in 8.3±4.6 days (p<0.001). 3) 1000 IEQs xenotransplanted into diabetic NOD/scid mice with and without IgM therapy resulted in return to normoglycemia in both groups. Removal of the kidney containing the islet graft at >60days post-transplant resulted in return of diabetes in Experiments 2 and 3. 4) 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 10.8±4.7 days. 5) Following intraportal transplantation, normoglycemia was restored in 6/6 IgM-treated mice. Controls turned diabetic in 6.3±2.5 days. 6) IgM diminished autoreactivity in NOD mice by reducing the percentage of marginal zone B cells, a subset associated with perpetuating 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) indicating reduction in autoreactive B cell activation. In humanized BLT mice, hIgM therapy expanded the Helios+Foxp3+Treg population.

*Conclusions: IgM therapy reversed new onset T1D by restoring immune homeostasis and diminishing autoreactivity. IgM therapy promoted permanent xenogeneic and allogeneic islet graft survival indicating its potential clinical relevance for cure of T1D by human islet allo or xeno transplantation.

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