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

• Published in: Diabetes (New York, N.Y.) Vol. 68; no. 6; pp. 1267 - 1276
• Main Authors: 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, Henderson, Courtney, Henry, Martha, Heyman, Kathleen, Hsiao, Belinda, Karges, Christina, Koziol, Beata-Gabriela, Lane, Lindsay, Liu, Shu, Lloyd, Jennifer
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.06.2019
• Subjects: CD4 antigen; CD8 antigen; Clinical trials; Colony-stimulating factor; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Flow cytometry; Globulins; Granulocyte colony-stimulating factor; Immunological tolerance; Immunology and Transplantation; Leukocytes (granulocytic); Lymphocytes T; PD-1 protein; Peptides; Thymocytes
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db19-0057

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.