IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes

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Abstract

Background IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.Methods We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years).Results There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.Conclusion Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial Registration ClinicalTrials.gov NCT02293837.Funding NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

Authors

Carla J. Greenbaum, Elisavet Serti, Katharina Lambert, Lia J. Weiner, Sai Kanaparthi, Sandra Lord, Stephen E. Gitelman, Darrell M. Wilson, Jason L. Gaglia, Kurt J. Griffin, William E. Russell, Philip Raskin, Antoinette Moran, Steven M. Willi, Eva Tsalikian, Linda A. DiMeglio, Kevan C. Herold, Wayne V. Moore, Robin Goland, Mark Harris, Maria E. Craig, Desmond A. Schatz, David A. Baidal, Henry Rodriguez, Kristina M. Utzschneider, Hendrik J. Nel, Carol L. Soppe, Karen D. Boyle, Karen Cerosaletti, Lynette Keyes-Elstein, S. Alice Long, Ranjeny Thomas, James G. McNamara, Jane H. Buckner, Srinath Sanda, for the ITN058AI EXTEND Study Team