Objective: To investigate whether polyclonal serum naturally occurring immunoglobulin M (nIgM) therapy prevents the onset and progression of autoimmune diabetes and promotes islet allograft survival.
Background: nIgM deficiency is associated with an increased tendency toward autoimmune disease development. Elevated levels of nIgM anti-leukocyte autoantibodies are associated with fewer graft rejections.
Methods: Four- to five-week-old female nonobese diabetic (NOD) littermates received intraperitoneal nIgM or phosphate-buffered saline/bovine serum albumin/immunoglobulin G (100 μg followed by 50–75 μg biweekly) until 18 weeks of age. C57BL/6 recipients of 300 BALB/c or 50 C57BL/6 islet grafts received saline or nIgM.
Results: Eighty percent control mice (n = 30) receiving saline became diabetic by 18 to 20 weeks of age. In contrast, none of 33 of nIgM-treated mice became diabetic (P < 0.0001). Discontinuing therapy resulted in hyperglycemia in only 9 of 33 mice at 22 weeks postdiscontinuation, indicating development of β-cell unresponsiveness. nIgM therapy initiated at 11 weeks of age resulted in hyperglycemia in only 20% of treated animals (n = 20) compared with 80% of controls (P < 0.0001). Treatment of mildly diabetic mice with nIgM (75 μg 3× per week) restored normoglycemia (n = 5), whereas severely diabetic mice required minimal dose islet transplant with nIgM to restore normoglycemia (n = 4). The mean survival time of BALB/c islet allografts transplanted in streptozotocin-induced diabetic C57BL/6 mice was 41.2 ± 3.3 days for nIgM-treated recipients (n = 4, fifth recipient remains normoglycemic) versus 10.2 ± 2.6 days for controls (n = 5) (P < 0.001). Also, after syngeneic transplantation, time taken to return to normoglycemia was 15.4 ± 3.6 days for nIgM-treated recipients (n = 5) and more than 35 days for controls (n = 4).
Conclusions: nIgM therapy demonstrates potential in preventing the onset and progression of autoimmune diabetes and in promoting islet graft survival.