Combination Treatment With Anti-CD20 and Oral Anti-CD3 Prevents and Reverses Autoimmune Diabetes

  1. Li Wen1
  1. 1Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
  2. 2Endocrinology Section, The 5th People’s Hospital, Fudan University, Shanghai, China
  3. 3Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, U.K.
  1. Corresponding author: Li Wen, li.wen{at}yale.edu.

Abstract

Type 1 diabetes (T1D) is a T cell–mediated autoimmune disease, although B cells also play an important role in T1D development. Both T cell– and B cell–directed immunotherapies have shown efficacy in the prevention and reversal of T1D. However, whether the combined strategy of targeting both T and B cells could further improve therapeutic efficacy remains to be explored. We show that combined treatment with intravenous antihuman CD20 (hCD20) and oral anti-CD3 significantly delays diabetes development in prediabetic hCD20 transgenic NOD mice. More importantly, the combined treatment reverses diabetes in >60% of mice newly diagnosed with diabetes. Further mechanistic studies demonstrated that the addition of oral anti-CD3 to the B-cell depletion therapy synergistically enhances the suppressive function of regulatory T cells. Of note, the oral anti-CD3 treatment induced a fraction of interleukin (IL)-10–producing CD4 T cells in the small intestine through IL-10– and IL-27–producing dendritic cells. Thus, the findings demonstrate that combining anti-CD20 and oral anti-CD3 is superior to anti-CD20 monotherapy for restoring normoglycemia in diabetic NOD mice, providing important preclinical evidence for the optimization of B cell–directed therapy for T1D.

Footnotes

  • Received August 29, 2012.
  • Accepted February 14, 2013.

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  1. Diabetes vol. 62 no. 8 2849-2858
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