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Resident macrophages of pancreatic islets have a seminal role in the initiation of autoimmune diabetes of NOD mice

  1. Emil R. Unanuea,2
  1. aDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
  1. Contributed by Emil R. Unanue, October 21, 2017 (sent for review August 1, 2017; reviewed by Pere Santamaria and David V. Serreze)


Our studies indicate that the resident macrophages of the pancreatic islets of Langerhans have a seminal role in the initiation and progression of autoimmune diabetes in NOD mice. In this study, islet macrophages were depleted by administration of a monoclonal antibody to the CSF-1 receptor. Macrophage depletion, either at the start of the autoimmune process or when diabetogenesis is active, leads to a significant reduction in diabetes incidence. Depletion of the islet macrophages reduces the entrance of T cells into islets and results in the absence of antigen presentation. Concordantly, a regulatory pathway develops that controls diabetes progression. We conclude that treatments that target the islet macrophages may have important clinical relevance for the control of autoimmune type 1 diabetes.


Treatment of C57BL/6 or NOD mice with a monoclonal antibody to the CSF-1 receptor resulted in depletion of the resident macrophages of pancreatic islets of Langerhans that lasted for several weeks. Depletion of macrophages in C57BL/6 mice did not affect multiple parameters of islet function, including glucose response, insulin content, and transcriptional profile. In NOD mice depleted of islet-resident macrophages starting at 3 wk of age, several changes occurred: (i) the early entrance of CD4 T cells and dendritic cells into pancreatic islets was reduced, (ii) presentation of insulin epitopes by dispersed islet cells to T cells was impaired, and (iii) the development of autoimmune diabetes was significantly reduced. Treatment of NOD mice starting at 10 wk of age, when the autoimmune process has progressed, also significantly reduced the incidence of diabetes. Despite the absence of diabetes, NOD mice treated with anti–CSF-1 receptor starting at 3 or 10 wk of age still contained variably elevated leukocytic infiltrates in their islets when examined at 20–40 wk of age. Diabetes occurred in the anti–CSF-1 receptor protected mice after treatment with a blocking antibody directed against PD-1. We conclude that treatment of NOD mice with an antibody against CSF-1 receptor reduced diabetes incidence and led to the development of a regulatory pathway that controlled autoimmune progression.


  • ?1J.A.C., D.P.M., S.T.F., and X.W. contributed equally to this work.

  • ?2To whom correspondence should be addressed. Email: unanue{at}wustl.edu.
  • Author contributions: J.A.C. and E.R.U. designed research; J.A.C., D.P.M., S.T.F., X.W., H.H., B.H.Z., and A.N.V. performed research; J.A.C., D.P.M., S.T.F., X.W., H.H., B.H.Z., A.N.V., and E.R.U. analyzed data; and J.A.C. and E.R.U. wrote the paper.

  • Reviewers: P.S., University of Calgary; and D.V.S., The Jackson Laboratory.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1713543114/-/DCSupplemental.

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