학술논문
IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes
Document Type
article
Author
Greenbaum, Carla J; Serti, Elisavet; Lambert, Katharina; Weiner, Lia J; Kanaparthi, Sai; Lord, Sandra; Gitelman, Stephen E; Wilson, Darrell M; Gaglia, Jason L; Griffin, Kurt J; Russell, William E; Raskin, Philip; Moran, Antoinette; Willi, Steven M; Tsalikian, Eva; DiMeglio, Linda A; Herold, Kevan C; Moore, Wayne V; Goland, Robin; Harris, Mark; Craig, Maria E; Schatz, Desmond A; Baidal, David A; Rodriguez, Henry; Utzschneider, Kristina M; Nel, Hendrik J; Soppe, Carol L; Boyle, Karen D; Cerosaletti, Karen; Keyes-Elstein, Lynette; Long, S Alice; Thomas, Ranjeny; McNamara, James G; Buckner, Jane H; Sanda, Srinath
Source
JCI Insight. 6(21)
Subject
Language
Abstract
BackgroundIL-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.MethodsWe 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).ResultsThere 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.ConclusionTocilizumab 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 RegistrationClinicalTrials.gov NCT02293837.FundingNIH 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.