Anti-CD3 immunotoxin prevents low-dose STZ/interferon-induced autoimmune diabetes in mouse

Diabetes. 1992 Apr;41(4):457-64. doi: 10.2337/diab.41.4.457.

Abstract

Autoimmune diabetes was induced with an established model in which 3 daily injections of 95 mg/kg body wt/day streptozocin (STZ) and 2 x 10(4) U interferon-gamma (IFN-gamma) were administered to C57BL/6 mice. Diabetes onset was accompanied by precipitous increases in serum glucose levels and validated by immunoperoxidase studies showing diminished islets in pancreatic tissue sections. Administration of two to three doses of a monoclonal antibody (MoAb) or an immunotoxin (IT) directed against the CD3 epsilon-chain before STZ/IFN-gamma treatment prevented increases in serum glucose and protected islets from damage. IT was made by crosslinking anti-CD3 to a low oligosaccharide-containing fraction of purified ricin toxin A chain (RTA; a catalytic inhibitor of protein synthesis) with a stabilized derivative of 2-iminothiolane. Protection was complete, long-lived, and selective because two different control ITs did not prevent diabetes onset. A second pan T-cell-reactive IT was synthesized by linking the MoAb anti-Ly1 to the same RTA toxin. Anti-Ly1 reacts with the murine homologue of human CD5. Anti-Ly1 RTA also protected against diabetes onset in a dose-dependent manner requiring higher doses and a longer schedule than anti-CD3 or anti-CD3 RTA. These studies demonstrate for the first time the importance of CD3+ and CD5+ cells in diabetes onset in the low-dose STZ/IFN-gamma model and show that anti-CD3, anti-CD3 RTA, or anti-CD5 RTA may be useful in vivo for the treatment of diabetes or perhaps other T-cell-mediated autoimmune diseases. These data may have important therapeutic implications for early autoimmune diabetes in humans.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • Antigens, CD / immunology
  • Antigens, Differentiation, T-Lymphocyte / immunology*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Autoimmune Diseases / prevention & control*
  • Blood Glucose / analysis
  • CD3 Complex
  • CD5 Antigens
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / prevention & control*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Flow Cytometry
  • Immunohistochemistry
  • Immunotoxins / immunology
  • Immunotoxins / physiology*
  • Insulin / analysis
  • Interferons / adverse effects*
  • Interferons / pharmacology
  • Islets of Langerhans / chemistry
  • Islets of Langerhans / immunology
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Antigen, T-Cell / immunology*
  • Streptozocin / adverse effects*
  • Streptozocin / pharmacology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Blood Glucose
  • CD3 Complex
  • CD5 Antigens
  • Immunotoxins
  • Insulin
  • Receptors, Antigen, T-Cell
  • Streptozocin
  • Interferons