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.
The therapeutic potential of murine polyclonal serum naturally occurring immunoglobulin M (nIgM) administration both in preventing the onset and progression of autoimmune type 1 diabetes in non-obese diabetic mice and in promoting graft survival after islet allotransplantation has been investigated. nIgM therapy prevents onset and progression of diabetes and promotes islet graft survival.
*Department of Surgery, Division of Transplantation
†Department of Medicine, Division of Nephrology, University of Virginia School of Medicine, Charlottesville, VA.
Reprints: Kenneth L. Brayman, MD, PhD, FACS, Department of Surgery, Division of Transplantation, University of Virginia School of Medicine, PO Box 800709, Charlottesville, VA 22908. E-mail: firstname.lastname@example.org.
Disclosure: The research was funded by the Focus to Cure Diabetes Foundation, 200 Garrett Street, Suite O, Charlottesville, VA 22902. The funding organization had no role in the design or conduct of this research. The authors declare no conflicts of interest. Patents are pending on naturally occurring IgM anti-leukocyte autoantibodies at the University of Virginia.