Use of anti-CD3 monoclonal antibody to induce immune regulation in type 1 diabetes

Ann N Y Acad Sci. 2004 Dec:1037:1-9. doi: 10.1196/annals.1337.001.

Abstract

Achieving immunologic tolerance to autoimmune diabetes is the goal of therapies for treatment and prevention of the disease. However, whether this can be achieved with an antigen-specific approach is still unproven in humans. Other approaches, including treatment with anti-CD3 monoclonal antibody, have focused on regulation of an active immune response. Preclinical studies with anti-CD3 mAb showed the ability to reverse diabetes and induce tolerance to autoimmunity, even at the time of presentation with hyperglycemia. These studies also suggested that mAb treatment induced an active regulatory process. Based on these and other preclinical data, we have carried out a Phase I/II trial of the humanized FcR non-binding anti-CD3 mAb hOKT3gamma1(Ala-Ala) in patients with new-onset type 1 diabetes. mAb treatment prevented the loss of insulin production over the first two years of the disease with reduced hemoglobin A1c levels and insulin usage. Studies have suggested that the mechanism of drug action involves induction of regulatory cells. CD4(+)IL-10(+) T cells can be found in patients after treatment; in addition, the CD8(+) T cells are induced by the mAb, and these cells may regulate antigen- specific responses. These initial studies have shown clinical efficacy of treatment with anti-CD3 mAb and suggest a novel mechanism that may account for the lasting effects of treatment.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • CD3 Complex / immunology
  • CD3 Complex / metabolism*
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Clinical Trials as Topic
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / therapy*
  • Glycated Hemoglobin / analysis
  • Humans
  • Immune Tolerance
  • Insulin / blood
  • Insulin / metabolism
  • Interleukin-10 / biosynthesis
  • Randomized Controlled Trials as Topic
  • Receptors, Fc / metabolism
  • Signal Transduction
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology

Substances

  • Antibodies, Monoclonal
  • CD3 Complex
  • Glycated Hemoglobin A
  • Insulin
  • Receptors, Fc
  • Interleukin-10