Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs

J Clin Invest. 2006 May;116(5):1371-81. doi: 10.1172/JCI27191. Epub 2006 Apr 20.

Abstract

Safe induction of autoantigen-specific long-term tolerance is the "holy grail" for the treatment of autoimmune diseases. In animal models of type 1 diabetes, oral or i.n. immunization with islet antigens induces Tregs that are capable of bystander suppression. However, such interventions are only effective early in the prediabetic phase. Here, we demonstrate that a novel combination treatment with anti-CD3epsilon-specific antibody and i.n. proinsulin peptide can reverse recent-onset diabetes in 2 murine diabetes models with much higher efficacy than with monotherapy with anti-CD3 or antigen alone. In vivo, expansion of CD25(+)Foxp3(+) and insulin-specific Tregs producing IL-10, TGF-beta, and IL-4 was strongly enhanced. These cells could transfer dominant tolerance to immunocompetent recent-onset diabetic recipients and suppressed heterologous autoaggressive CD8 responses. Thus, combining a systemic immune modulator with antigen-specific Treg induction is more efficacious in reverting diabetes. Since Tregs act site-specifically, this strategy should also be expected to reduce the potential for systemic side effects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Animals
  • Autoantigens / administration & dosage
  • Autoantigens / therapeutic use*
  • CD3 Complex / chemistry*
  • CD3 Complex / immunology
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Diabetes Mellitus, Type 1 / therapy*
  • Interleukin-10 / biosynthesis
  • Interleukin-4 / biosynthesis
  • Mice
  • Mice, Transgenic
  • Proinsulin / administration & dosage
  • Proinsulin / therapeutic use*
  • Remission Induction
  • T-Lymphocytes, Regulatory / metabolism*
  • Transforming Growth Factor beta / biosynthesis

Substances

  • Autoantigens
  • CD3 Complex
  • Cd3e protein, mouse
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interleukin-4
  • Proinsulin