The pathogenesis of adoptive murine autoimmune diabetes requires an interaction between alpha 4-integrins and vascular cell adhesion molecule-1

J Clin Invest. 1994 Apr;93(4):1700-8. doi: 10.1172/JCI117153.

Abstract

An adoptive transfer model of insulin-dependent diabetes mellitus (IDDM) in the nonobese diabetic mouse was used to examine the roles of alpha 4-integrin, vascular cell adhesion molecule 1 (VCAM-1); and intercellular adhesion molecule 1 (ICAM-1) in the pathogenesis of autoimmune diabetes. Antibodies specific for both alpha 4-integrin and one of its ligands, VCAM-1, were able to delay onset of diabetes and decrease the incidence of the disease in adoptive transfer studies. This blocking of disease was accompanied by a marked decrease in lymphocytic infiltration of the islets of Langerhans. Furthermore, these antibodies preferentially block entrance of CD4 T cells into the tissue. Antibodies specific for ICAM-1 had little effect on the onset or incidence of IDDM. Thus, we conclude that an alpha 4-integrin-VCAM-1 interaction is important in T cell entry into the islets of Langerhans and in the pathogenesis of IDDM. In addition, the cascade of events leading to T cell transit across endothelium may be different for CD4 and CD8 cells, and may differ depending on the endothelium involved. Our results support the more general conclusion that an alpha 4-integrin-VCAM-1 interaction may be crucial in allowing activated effector CD4T cells to leave the blood and enter tissue to clear infection.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • CD4-CD8 Ratio
  • Cell Adhesion Molecules / analysis
  • Cell Adhesion Molecules / physiology*
  • Diabetes Mellitus, Type 1 / etiology*
  • Immunotherapy, Adoptive
  • Integrins / analysis
  • Integrins / physiology*
  • Intercellular Adhesion Molecule-1
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred NOD
  • Receptors, Very Late Antigen / physiology
  • Spleen / immunology
  • T-Lymphocytes / chemistry
  • T-Lymphocytes / pathology
  • T-Lymphocytes / physiology*
  • Vascular Cell Adhesion Molecule-1

Substances

  • Antibodies, Monoclonal
  • Cell Adhesion Molecules
  • Integrins
  • Receptors, Very Late Antigen
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1