726 Deciphering the mechanism of action of polyclonal IgM immunotherapy in the prevention of type 1 diabetes onset and progression as well as in the promotion of longitudinal syngeneic and allogeneic islet graft survival following transplantation.
Wednesday November 18, 2015 from 11:00 to 12:30
Plenary Room 1

Kenneth L. Brayman, United States

Professor of Surgery, Medicine and Biomedical Engineering

Surgery, Transplant Division

University of Virginia


Deciphering the mechanism of action of polyclonal IgM immunotherapy in the prevention of type 1 diabetes onset and progression as well as in the promotion of longitudinal syngeneic and allogeneic islet graft survival following transplantation

Preeti Chhabra1, Stephen Owen3, Christopher Wilson3, Andrew Marshall3, Peter I. Lobo2, Daniel J. Moore3, Kenneth Brayman1.

1Surgery, University of Virginia, Charlottesville, VA, United States; 2Medicine, University of Virginia, Charlottesville, VA, United States; 3Pediatrics, Vanderbilt University, Nashville, TN, United States

Goal: To elucidate the cellular mechanism of polyclonal IgM immunotherapy by defining its specific effects on immune cell subsets that regulate islet immunity.
Background: The prevention or reversal of type 1 diabetes (T1D) and the promotion of permanent longitudinal graft survival following islet or pancreas transplantation in the absence of chronic immunosuppression is the ultimate goal in the cure of T1D. IgM immunotherapy prevents the onset and progression of T1D and in conjunction with islet transplantation, both reverses and prevents its recurrence. It also promotes longitudinal islet graft survival. Purified IgM inhibits T-cell activation and proliferation as well as leukocyte chemotaxis and the production of some proinflammatory cytokines, indicating an innate mechanism that down-regulates T-cell–mediated inflammatory responses[1].
Methods: 1) 4-5 wks-old female NOD littermates received intraperitoneal (i.p.) mouse or human IgM (mIgM, hIgM) or saline/bovine serum albumin/IgG (100μg followed by 50–75μg biweekly) until 18 weeks of age. 2) C57BL/6 recipients of 300 BALB/c or 50 C57BL/6 islet grafts received saline or IgM. 3) 4-5 wks-old C57BL/6 and NOD mice or humanized BLT mice were injected with 100ug mouse or human IgM (i.p.) initially, followed by 65ug on Day5 and Day10. Splenocytes and bone marrow cells were harvested on Day13 and analyzed by flow cytometry.
Results: Both mIgM and hIgM prevented the progression of autoimmune diabetes in NOD mice. 80% control mice (n=30) receiving saline became diabetic by 18 to 20 weeks of age. In contrast, none of mouse or human IgM-treated mice (n=33 and n=15) became diabetic (P<0.0001). Discontinuing therapy resulted in hyperglycemia in only 9 of 33 mice at 22-weeks post-discontinuation, indicating the development of β-cell unresponsiveness. IgM therapy increased the mean survival time of BALB/c islet allografts transplanted in diabetic C57BL/6 mice from 10.2±2.6 days for controls (n=5) to 41.2±3.3 days (n=4, fifth recipient remains normoglycemic) (P<0.001). Following syngeneic transplantation, time taken to return to normoglycemia was 15.4±3.6 days for IgM-treated recipients (n=5) and more than 35 days for controls (n=4). mIgM therapy significantly expanded total splenic B cells in NOD mice while in bone marrow, it reduced immature splenic transitional B cells and depleted immature and mature B cells. In spleen, B cell numbers in NOD mice were restored to the levels seen in C57BL/6 mice; this increase was associated with a 2-fold rise in BAFF levels in treated NOD but not C57BL/6 mice. The mechanism by which mIgM corrects B cell lymphopenia in NOD mice and restores homeostasis may relate to increased levels of IgM Fc-Receptor (TOSO) expression by splenic B lymphocytes, particularly transitional B cells, indicating that mIgM may interact with B lymphocytes via TOSO at this critical selection point. Furthermore, IgM therapy expanded regulatory cells including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). hIgM also significantly expanded Tregs in humanized BLT mice confirming its beneficial effect.
Conclusions: IgM therapy restores immune homeostasis in T1D via expansion of the MDSC and Treg compartments and correction of the B cell lymphopenia that undermines immune selection in NOD mice. This beneficial effect may be readily translatable to patients with T1D or islet graft recipients as evidenced in our preclinical model of human immunology.

Focus to Cure Diabetes Foundation.


[1] Lobo et al. in J Immunol. 2008 Feb 1;180(3): 1780-91.

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