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

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 HarrisMaria 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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish (US)
Article numbere150074
JournalJCI Insight
Issue number21
StatePublished - Nov 8 2021

Bibliographical note

Funding Information:
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.

Funding Information:
The EXTEND trial was conducted by the ITN, which is supported by the NIDDK and the NIAID of the NIH under award number UM1AI109565. This project was in part supported by these grants/awards: at UCSF by UL1TR000004 from NIH/NCRR CTSA; at Joslin by P30DK036836 from NIH/NIDDK; at the University of South Florida by NIH/NIDDK U01DK103266; at the University of Florida by U01DK103266 from NIH/NIDDK and 1UL1TR000064 from NIH/NCRR CTSA; at Children’s Hospital of Philadelphia by UL1TR001878 from NIH/NCATS; at University of Iowa by UL1TR002537 NIH/CTSA; at Children’s Hospital at Westmead MEC is supported by a National Health and Medical Research Council Practitioner Fellowship (APP1136735); at the University of Minnesota by U01-DK085476 from NIH/NIDDK and UL1-TR002494 from NIH/CTSA; at Indiana University by Clinical and Translational Science Institute Award UL1TR002529; UL1TR000445 Vanderbilt Institute for Clinical and Translational Research; at Stanford University by NCATS/NIH UL1TR003142; and at the University of Minnesota by NIH CTSA program UL1-TR002494. KMU is supported by the Veteran Affairs Administration. JHB and KL are supported by NIAID/ NIH 1R01AI132774. DMW received support from the NIH TrialNet group. AM has research funding totaling more than $50,000 in 2020 from the NIH (TrialNet subcontract with the University of South Florida, an R01, and a T32), the Cystic Fibrosis Foundation, and the JDRF.

Publisher Copyright:
© 2021, Greenbaum et al.


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