A Preclinical Consortium Approach for Assessing the Efficacy of Combined Anti-CD3 Plus IL-1 Blockade in Reversing New-Onset Autoimmune Diabetes in NOD Mice

Diabetes. 2016 May;65(5):1310-6. doi: 10.2337/db15-0492. Epub 2015 Dec 30.

Abstract

There is an ongoing need to develop strategic combinations of therapeutic agents to prevent type 1 diabetes (T1D) or to preserve islet β-cell mass in new-onset disease. Although clinical trials using candidate therapeutics are commonly based on preclinical studies, concern is growing regarding the reproducibility as well as the potential clinical translation of reported results using animal models of human disorders. In response, the National Institutes of Health Immune Tolerance Network and JDRF established a multicenter consortium of academic institutions designed to assess the efficacy and intergroup reproducibility of clinically applicable immunotherapies for reversing new-onset disease in the NOD mouse model of T1D. Predicated on prior studies, this consortium conducted coordinated, prospective studies, using joint standard operating procedures, fixed criteria for study entry, and common reagents, to optimize combined anti-CD3 treatment plus interleukin-1 (IL-1) blockade to reverse new-onset disease in NOD mice. We did not find that IL-1 blockade with anti-IL-1β monoclonal antibody or IL-1trap provided additional benefit for reversing new-onset disease compared with anti-CD3 treatment alone. These results demonstrate the value of larger, multicenter preclinical studies for vetting and prioritizing therapeutics for future clinical use.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / therapeutic use
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • Biomedical Research / methods
  • CD3 Complex / chemistry*
  • CD3 Complex / metabolism
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • Immunoglobulin Fab Fragments / administration & dosage
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / therapeutic use
  • Immunotherapy / methods
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / immunology
  • Insulin-Secreting Cells / metabolism
  • Interleukin-1 Receptor Accessory Protein / antagonists & inhibitors
  • Interleukin-1 Receptor Accessory Protein / metabolism
  • Interleukin-1beta / antagonists & inhibitors*
  • Interleukin-1beta / metabolism
  • Mice, Inbred NOD
  • Multicenter Studies as Topic
  • Pilot Projects
  • Receptors, Interleukin-1 Type I / antagonists & inhibitors
  • Receptors, Interleukin-1 Type I / metabolism
  • Recombinant Fusion Proteins / therapeutic use
  • Reproducibility of Results
  • Research Design
  • Specific Pathogen-Free Organisms
  • United States

Substances

  • Antibodies, Monoclonal
  • CD3 Complex
  • IL1B protein, mouse
  • Immunoglobulin Fab Fragments
  • Insulin
  • Interleukin-1 Receptor Accessory Protein
  • Interleukin-1beta
  • Receptors, Interleukin-1 Type I
  • Recombinant Fusion Proteins
  • rilonacept