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Naturally occurring Immunoglobulin M (nIgM) Auto-Antibodies prevent Autoimmune Diabetes and Mitigate Inflammation following Transplantation.
Preeti Chhabra*, Kailo Schlegel*, Mark D. Okusa*, Peter I. Lobo*, Kenneth L. Brayman
University Of Virginia, Charlottesville, VA

OBJECTIVE(S): nIgM deficiency is associated with an increased tendency towards autoimmune disease development. Elevated levels of nIgM anti-leucocyte autoantibodies are associated with fewer graft rejections. Studies indicate that Tregs are ineffective in controlling TH-17 mediated inflammation in auto-immune insulitis in type 1 diabetes (T1D) and in allograft rejection. Purified serum nIgM binds to CD3, CD4, CXCR4, CCR5 and inhibits Tcell activation, proliferation and differentiation into TH-1 and TH-I7. Therefore, we investigated if purified serum nIgM could prevent the onset/progression of T1D and mitigate inflammation following allotransplantation.
METHODS: 6-7wk-old female NOD litter-mates received saline/BSA (controls;n=30) or 100ug nIgM intraperitoneal (test;n=23) followed by 50ugs nIgM biweekly for 18wks. B6 cardiac allograft recipients received saline or nIgM.
RESULTS: 80% control mice became diabetic by 18-20wks of age. In contrast, 0/23 of nIgM-treated mice became diabetic (p<0.001). Discontinuing therapy resulted in hyperglycemia in only 8/23 mice at 22wks post-discontinuation (p<0.01), indicating possible development of tolerance. nIgM therapy initiated at 11wks of age resulted in hyperglycemia in only 20% of nIgM-treated animals (n=10) compared to 80% of controls (p<0.001). Treatment of mildly diabetic mice with nIgM (75ugx3/wk) restored normoglycemia (n=5) while severely diabetic mice (glucose>350mg/dl) required minimal dose islet transplant (75IEQ) with nIgM to restore normoglycemia (n=3). In allotransplant studies, control WT-B6 recipients (n=7) rejected Balb/c cardiac allografts by 5-7days with histology demonstrating abundant TH-17cells, while recipients(n=6) receiving IgM biweekly, beginning 24hrs post-transplantation, had none/minimal rejection (p<0.01).
CONCLUSIONS: nIgM therapy has therapeutic potential in preventing the onset/progression of T1D and in mitigating inflammation in transplantation.


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