학술논문
Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA1c, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data
Document Type
article
Author
Haller, Michael J; Long, S Alice; Blanchfield, J Lori; Schatz, Desmond A; Skyler, Jay S; Krischer, Jeffrey P; Bundy, Brian N; Geyer, Susan M; Warnock, Megan V; Miller, Jessica L; Atkinson, Mark A; Becker, Dorothy J; Baidal, David A; DiMeglio, Linda A; Gitelman, Stephen E; Goland, Robin; Gottlieb, Peter A; Herold, Kevan C; Marks, Jennifer B; Moran, Antoinette; Rodriguez, Henry; Russell, William E; Wilson, Darrell M; Greenbaum, Carla J; Battaglia, Manuela; Becker, Dorothy; Bingley, Penelope; Bosi, Emanuele; Buckner, Jane; Clements, Mark; Colman, Peter G; DiMeglio, Linda; Evans-Molina, Carmella; Gottlieb, Peter; Herold, Kevan; Knip, Mikael; Lernmark, Ake; Moore, Wayne; Muir, Andrew; Palmer, Jerry; Peakman, Mark; Philipson, Louis; Raskin, Philip; Redondo, Maria; Russell, William; Sosenko, Jay M; Spain, Lisa; Wentworth, John; Wherrett, Diane; Winter, William; Ziegler, Anette; Anderson, Mark; Antinozzi, Peter; Insel, Richard; Kay, Thomas; Pugliese, Alberto; Roep, Bart; Toppari, Jorma; Leschek, Ellen; Bourcier, Katarzyna; Ridge, John; Rafkin, Lisa; Santiago, Irene; Bundy, Brian; Abbondondolo, Michael; Adams, Timothy; Asif, Ilma; Bjellquist, Jenna; Boonstra, Matthew; Burroughs, Cristina; Cleves, Mario; Cuthbertson, David; DeSalvatore, Meagan; Eberhard, Christopher; Fiske, Steve; Ford, Julie; Garmeson, Jennifer; Geyer, Susan; Hays, Brian
Source
Diabetes. 68(6)
Subject
Language
Abstract
A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.