Anti-CD3/Anti-CXCL10 Antibody Combination Therapy Induces a Persistent Remission of Type 1 Diabetes in Two Mouse Models

Diabetes. 2015 Dec;64(12):4198-211. doi: 10.2337/db15-0479. Epub 2015 Aug 20.

Abstract

Anti-CD3 therapy of type 1 diabetes results in a temporary halt of its pathogenesis but does not constitute a permanent cure. One problem is the reinfiltration of islets of Langerhans with regenerated, autoaggressive lymphocytes. We aimed at blocking such a reentry by neutralizing the key chemokine CXCL10. Combination therapy of diabetic RIP-LCMV and NOD mice with anti-CD3 and anti-CXCL10 antibodies caused a substantial remission of diabetes and was superior to monotherapy with anti-CD3 or anti-CXCL10 alone. The combination therapy prevented islet-specific T cells from reentering the islets of Langerhans and thereby blocked the autodestructive process. In addition, the local immune balance in the pancreas was shifted toward a regulatory phenotype. A sequential temporal inactivation of T cells and blockade of T-cell migration might constitute a novel therapy for patients with type 1 diabetes.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / therapeutic use*
  • Autoimmunity / drug effects*
  • CD3 Complex / chemistry*
  • CD3 Complex / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chemokine CXCL10 / antagonists & inhibitors*
  • Chemokine CXCL10 / metabolism
  • Crosses, Genetic
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Disease Models, Animal*
  • Drug Therapy, Combination
  • Female
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / immunology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Lymphocyte Activation / drug effects
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Remission Induction
  • Spleen / drug effects
  • Spleen / pathology
  • Survival Analysis

Substances

  • Antibodies, Monoclonal
  • CD3 Complex
  • Chemokine CXCL10
  • Cxcl10 protein, mouse
  • Hypoglycemic Agents