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Immunology and Transplantation

Healthy Donor Polyclonal IgMs Diminish B-Lymphocyte Autoreactivity, Enhance Regulatory T-Cell Generation, and Reverse Type 1 Diabetes in NOD Mice

  1. Christopher S. Wilson1,
  2. Preeti Chhabra2,
  3. Andrew F. Marshall3,
  4. Caleigh V. Morr3,
  5. Blair T. Stocks1,
  6. Emilee M. Hoopes3,
  7. Rachel H. Bonami4,
  8. Greg Poffenberger5,
  9. Kenneth L. Brayman2 and
  10. Daniel J. Moore1,3⇑
  1. 1Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN
  2. 2Department of Surgery, University of Virginia, Charlottesville, VA
  3. 3Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, TN
  4. 4Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN
  5. 5Department of Medicine, Division of Endocrinology, Vanderbilt University Medical Center, Nashville, TN
  1. Corresponding author: Daniel J. Moore, daniel.moore{at}vanderbilt.edu.
Diabetes 2018 Nov; 67(11): 2349-2360. https://doi.org/10.2337/db18-0456
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Abstract

Autoimmune diseases such as type 1 diabetes (T1D) arise from unrestrained activation of effector lymphocytes that destroy target tissues. Many efforts have been made to eliminate these effector lymphocytes, but none has produced a long-term cure. An alternative to depletion therapy is to enhance endogenous immune regulation. Among these endogenous alternatives, naturally occurring Igs have been applied for inflammatory disorders but have lacked potency in antigen-specific autoimmunity. We hypothesized that naturally occurring polyclonal IgMs, which represent the majority of circulating, noninduced antibodies but are present only in low levels in therapeutic Ig preparations, possess the most potent capacity to restore immune homeostasis. Treatment of diabetes-prone NOD mice with purified IgM isolated from Swiss Webster (SW) mice (nIgMSW) reversed new-onset diabetes, eliminated autoreactive B lymphocytes, and enhanced regulatory T-cell (Treg) numbers both centrally and peripherally. Conversely, IgM from prediabetic NOD mice could not restore this endogenous regulation, which represents an unrecognized component of T1D pathogenesis. Of note, IgM derived from healthy human donors was similarly able to expand human CD4 Tregs in humanized mice and produced permanent diabetes protection in treated NOD mice. Overall, these studies demonstrate that a potent, endogenous regulatory mechanism, nIgM, is a promising option for reversing autoimmune T1D in humans.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-0456/-/DC1.

  • Received April 20, 2018.
  • Accepted August 12, 2018.
  • © 2018 by the American Diabetes Association.
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Healthy Donor Polyclonal IgMs Diminish B-Lymphocyte Autoreactivity, Enhance Regulatory T-Cell Generation, and Reverse Type 1 Diabetes in NOD Mice
Christopher S. Wilson, Preeti Chhabra, Andrew F. Marshall, Caleigh V. Morr, Blair T. Stocks, Emilee M. Hoopes, Rachel H. Bonami, Greg Poffenberger, Kenneth L. Brayman, Daniel J. Moore
Diabetes Nov 2018, 67 (11) 2349-2360; DOI: 10.2337/db18-0456

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Healthy Donor Polyclonal IgMs Diminish B-Lymphocyte Autoreactivity, Enhance Regulatory T-Cell Generation, and Reverse Type 1 Diabetes in NOD Mice
Christopher S. Wilson, Preeti Chhabra, Andrew F. Marshall, Caleigh V. Morr, Blair T. Stocks, Emilee M. Hoopes, Rachel H. Bonami, Greg Poffenberger, Kenneth L. Brayman, Daniel J. Moore
Diabetes Nov 2018, 67 (11) 2349-2360; DOI: 10.2337/db18-0456
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