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

Ronald G Gill; Philippe P Pagni; Tinalyn Kupfer; Clive H Wasserfall; Songyan Deng; Amanda Posgai; Yulia Manenkova; Amira Bel Hani; Laura Straub; Philip Bernstein; Mark A Atkinson; Kevan C Herold; Matthias von Herrath; Teodora Staeva; Mario R Ehlers; Gerald T Nepom

doi:10.2337/db15-0492

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.

Authors

Ronald G Gill¹, Philippe P Pagni², Tinalyn Kupfer³, Clive H Wasserfall⁴, Songyan Deng⁵, Amanda Posgai⁴, Yulia Manenkova², Amira Bel Hani², Laura Straub⁶, Philip Bernstein⁷, Mark A Atkinson⁴, Kevan C Herold⁵, Matthias von Herrath², Teodora Staeva⁸, Mario R Ehlers⁶, Gerald T Nepom⁹

Affiliations

¹ Departments of Surgery and Immunology, University of Colorado Denver, Aurora, CO ronald.gill@ucdenver.edu.
² La Jolla Institute for Allergy and Immunology, La Jolla, CA.
³ Departments of Surgery and Immunology, University of Colorado Denver, Aurora, CO.
⁴ Department of Pathology, University of Florida, Gainesville, FL.
⁵ Yale University School of Medicine, New Haven, CT.
⁶ Immune Tolerance Network, University of California, San Francisco, San Francisco, CA.
⁷ Immune Tolerance Network, Bethesda, MD.
⁸ JDRF, New York, NY.
⁹ Benaroya Research Institute, Seattle, WA.

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

Grants and funding

UM1 AI109565/AI/NIAID NIH HHS/United States